Bi-heteroaryl compounds as Vps34 inhibitors

ABSTRACT

The present invention includes novel methods of treating a disease or disorder characterized by hyperactivity of Vps34, and compound as Vps34 inhibitors; particularly compounds of Formula I or a pharmaceutically acceptable salt thereof, as well as methods of treating a disease, disorder, or syndrome associated with Vps34 inhibition, particularly hyperproliferative diseases. The present invention also includes pharmaceutical compositions including compounds of formula I and pharmaceutically acceptable salts thereof.

FIELD OF INVENTION

The present invention relates to bi-hetereoaryl compounds that inhibitthe Vps34 enzyme and uses thereof for the treatment of diseasesassociated with such inhibition. Consequently, the present inventionincludes bi-heteroaryl compounds, compositions thereof, methods of theiruse, and methods of their manufacture, where such compounds aregenerally pharmacologically useful in therapies whose mechanism ofaction rely on the inhibition of Vps34, and more particularly intherapies for the treatment of proliferative diseases, including cancer.

BACKGROUND

Phosphoinositide 3-kinases (hereafter, “PI3Ks”) are enzymes thatphosphorylate the 3-hydroxyl position of the inositol ring ofphosphoinositides (“PIs”), and are involved in diverse cellular eventssuch as cell migration, cell proliferation, oncogenic transformation,cell survival, signal transduction, and intracellular trafficking ofproteins. In yeast (S. cerevisiae), Vps34 (“vacuolar protein sorting34”) encodes a PI 3-kinase gene product that mediates the activediversion of proteins from the secretory pathway to vacuoles; mammalshave a corresponding family of PI3-kinases, including three classes ofPI3Ks, with a variety of isoforms and types within. The closest humanhomolog of yeast Vps34 is an 887 residue protein called PI3Kclass3(“PI3KC3”)(also referred to herein as “hVps34,” for human Vps34), whichshares about 37% sequence identity with the yeast protein over its fulllength (Volinia et al. (1995) EMBO J. 14(14): 3339).

hVps34 is the enzymatic component of a multiprotein complex thatincludes a ser/thr kinase called Vps15p, and proautophagic tumorsuppressors Beclin1/Atg6, and UVRAG, and Bif-1 in mammals (Vps15, Atg6,and Atg 14 in yeast)(Mari et al. (2007) Cell Biol. 9:1125). Of the threeclasses of PI3 kinase this has the most restricted substratespecificity, being strictly limited to PtdIns. Like class IAPI3-kinases, PI3KC3s (e.g., hVps34) play a well recognized role in theregulation of S6K1, and hence in nutrient-sensing.

The Vps34 gene product (Vps34p) is an enzyme required for proteinsorting to the lysosome-like vacuole of the yeast, and appears toregulate intracellular protein trafficking decisions. Vps34p sharessignificant sequence similarity with the catalytic subunit of bovinephosphatidylinositol (PI) 3-kinase (the p110 subunit), which is known tointeract with activated cell surface receptor tyrosine kinases. Yeaststrains deleted for the Vps34 gene or carrying Vps34 point mutationslacked detectable PI 3-kinase activity and exhibited severe defects invacuolar protein sorting. Overexpression of Vps34p resulted in anincrease in PI 3-kinase activity, and this activity was specificallyprecipitated with antisera to Vps34p (Schu et al. (1993) Science 260(5104): 88). hVps34 is an integral part of the autophagy process, oreukaryotic cell mechanism for cytoplasmic renewal. Autophagy is acellular catabolic degradation response to starvation or stress wherebycellular proteins, organelles, and cytoplasm are engulfed, digested, andrecycled to sustain cellular metabolism. Autophagy is characterized bythe engulfment of cytoplasmic material into specialized double-membranevesicles known as autophagosomes. The degradation of cellularcytoplasmic components helps eukaryotic cells jettison defectiveorganelles and protein complexes (Yorimitsu et al (2005) Cell DeathDiffer. 12:1542). Nonselective autophagy can be initiated by starvation,allowing cells to convert organelles and proteins into nutrients forsurvival. Autophagy can also be employed to kill cells, in addition toor instead of apoptosis, for instance (Neufeld et al (2008) Autophagy).

Parodoxically, certain pathologies feature autophagy processes, such astumorigenesis, aging, and neurodegeneration (Huang et al. (2007) CellCycle 6:1837). Cell death resulting from progressive cellularconsumption has been attributed to unmitigated autophagy (Baehrecke etal. (2005) Nature Rev. Mol. Cell. Biol. 6:505). Autophagy is thought toprolong the survival of tumor cells defective in apoptosis, e.g.,protecting them from metabolic stress. Inhibiting autophagy, and therebysensitizing cells (e.g., apoptosis-resistant cells) to metabolic stressrepresents a promising tumor therapy regimen (Mathew et al. (2007)Nature Reviews 7:961). Known inhibitors of autophagy, includingWortmannin and 3-methyladenine, target and inhibit hVps34 (Petiot et al.(2000) J. Biol. Chem. 275:992).

Consistent with the autophagy and cancer link is recognition in thefield that constitutive activation of PI3Ks is responsible for at leastovarian, head and neck, urinary tract, cervical and small cell lungcancers. PI3K signaling can be attenuated by the phosphatase activity ofthe tumor suppressor PTEN (phosphatase and tensin homologue detected inchromosome 10), which is absent in a number of human cancers. InhibitingPI3K arrests a major cancer cell survival signaling pathway andovercomes the absence of tumor suppressor PTEN, providing antitumoractivity and increased tumor sensitivity to a wide variety of drugs(Stein et al. (2001) Endocrine-Related Cancer 8:237).

SUMMARY

Compounds of formula (I), or a pharmaceutically acceptable salt thereof,are provided herein:

wherein

R¹ is C₁₋₆alkyl, NR³R⁶, C₁₋₆alkoxy, or —S—C₁₋₆alkyl;

R² is C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, a C₆₋₁₄aryl group, aC₃₋₁₄cycloalkyl group, a 5 to −14 membered heteroaryl containing 1 to 3heteroatoms each independently selected from N, O, and S, C₁₋₆alkoxy,C₂₋₆-alkenyloxy, C₂₋₆-alkynyloxy, C₁₋₆alkyl-O—R²⁷,C₁₋₆alkyl-C₃₋₁₄cycloalkyl, C₁₋₆alkyl-O—C₀₋₆alkyl-C₆₋₁₄aryl,C₁₋₆alkyl-O—SiR⁸R⁹R¹⁰, halogen, or C₁₋₆haloalkyl, wherein R² may beunsubstituted or substituted with OH, C1-6alkoxy, or halogen;

R⁴ and R⁵ are each independently H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₆₋₁₄aryl, C₃₋₁₄cycloalkyl, a 3 to 14-membered cycloheteroalkylcontaining 1 to 3 heteroatoms each independently selected from N, O, andS, a 5 to −14 membered heteroaryl containing 1 to 3 heteroatoms eachindependently selected from N, O, and S, C₁₋₆alkoxy, OH,C₁₋₆alkylNR¹¹R¹², C₁₋₆alkyl-O—R¹³, C₁₋₆alkyl-5 to 14-membered heteroarylcontaining 1 to 3 heteroatoms each independently selected from N, O, andS, or C(O)—C₁₋₆alkyl, wherein said C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₆₋₁₄aryl group, C₃₋₁₄cycloalkyl group, 3 to 14-memberedcycloheteroalkyl group, 5- to 14-membered heteroaryl group, C₁₋₆alkoxy,C₁₋₆alkyl-NR¹¹R¹², C₁₋₆alkylOR¹³, C₁₋₆alkyl-5- to 14-membered heteroarylgroup, or C(O)—C₁₋₆alkyl is optionally substituted by one or moresubstituents selected from the group consisting of halogen, a 5- to14-membered heteroaryl containing 1 to 3 heteroaroms each independentlyselected from O, N, and S, —OH, C₁₋₆alkyl, C₁₋₆haloalkyl,—C₁₋₆alkylOR²⁷, C₁₋₆alkoxy, —NR¹⁴R¹⁵, —C(O)NR¹⁶R¹⁷, —NR¹⁸C(O)R¹⁹,—NR²⁰C(O)OR²¹, —C(O)R²², —C(O)OR²³, —CN, —SO₂R²⁶, —O—, and —NR²⁴SO₂R²⁵;

R³ and R⁶ are independently H, C₁₋₆alkyl, C₁₋₆alkyl-C₆₋₁₄aryl,C₁₋₆alkoxy, a C₃₋₁₄cycloalkyl, a 3- to 14-membered cycloheteroalkylcontaining 1 to 3 heteroatoms each independently selected from O, N andS, a C₆₋₁₄aryl, a 5- to 14-membered heteroaryl containing 1 to 3heteroatoms each independently selected from O, N, or S, orC₁₋₆alkyl-O—R⁸, wherein C₁₋₆alkyl, C₁₋₆alkyl-C₆₋₁₄aryl, C₁₋₆alkoxy, aC₃₋₁₄cycloalkyl group, a 3- to 14-membered cycloheteroalkyl group, aC₆₋₁₄aryl group, a 5- to 14-membered heteroaryl group, or—C₁₋₆alkyl-O—R⁸, may be substituted by one of more of C₁₋₆alkyl, and OH;

R¹¹ and R¹² are each independently hydrogen, C₁₋₆alkyl, C₃₋₈cycloalkyl,C₆₋₁₄ aryl, 5- to 14-membered heteroaryl containing 1 to 3 heteroatomseach independently selected from O, N or S, 3- to 14-memberedcycloheteroalkyl containing 1 to 3 heteroatoms each independentlyselected from O, N, or S, or NR¹¹R¹² forms a non-aromatic four to sevenmembered ring optionally containing a second heteroatom selected from O,N and S, and optionally substituted by one or more substituents R²⁸(preferably mono or di-substituted).

R⁷ and R^(7a) are independently H, C₁₋₆alkyl, halogen, OH, orC₁₋₆alkoxy.

n is 0, 1, or 2; and

R⁸, R⁹, R¹⁰, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³,R²⁴, R²⁵, R²⁶, R²⁷, and R²⁸ are each independently H, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₆₋₁₄ aryl, C₃₋₁₄ cycloalkyl, 3- to14-membered cycloheteroalkyl containing 1 to 3 heteroatoms selected fromO, N or S, or a 5- to 14-membered heteroaryl containing 1 to 3heteroatoms selected from O, N, or S.

The following specific embodiments of the invention according to formula(I) may be incorporated into the definition of formula (I) and combinedin any number of suitable ways.

In an embodiment, R⁷ and R^(7a) are H or C₁₋₆alkyl, such as methyl,ethyl, propyl, or butyl. In another embodiment, R⁷ is H or methyl, andin yet another embodiment, R⁷ is H. In an embodiment, n is 0 or 1. Inanother embodiment, n is 0.

In an embodiment, R¹ is C₁₋₆alkyl, such as methyl, ethyl, or propyl;C₁₋₆alkoxy, such as methoxy, or ethoxy; —S—C₁₋₆alkyl, such as —SCH₃, or—SCH₂CH₃, or —NR³R⁶, where R³ and R⁶ are independently H, or C₁₋₆alkyl,such as methyl, ethyl, propyl, isopropyl, butyl, or pentyl;C₁₋₆alkyl-aryl, such as benzyl or ethyl-phenyl; C₁₋₆alkoxy, such asmethoxy or ethoxy; a C₃₋₁₄cycloalkyl group (e.g., cyclopropyl,cyclopentyl, or cyclohexyl); a 3- to 14-membered cycloheteroalkylcontaining 1 to 3 heteroatoms selected from O, S or N (e.g.,moprholinyl, tetrahydropyranyl, tetrahydrofuranyl, piperidinyl, orpiperazinyl); a C₆₋₁₄aryl group (e.g., phenyl); a 5- to 14-memberedheteroaryl containing 1 to 3 heteroatoms selected from O, S or N (e.g.,pyridinyl, pyrazinyl, or pyrimidyl); or —C₁₋₆alkyl-O—R⁸, where R⁸ is Hor C₁₋₆alkyl (e.g., —CH₂—OH, —CH₂CH₂—OH, —CH₂CH₂CH₂OH, —CH(CH₃)CH₂—OH,—CH₂CH(CH₃)—OH), —CH₂OCH₃, —CH₂CH₂—O—CH₃, and so on).

In another embodiment, R¹ is methyl, ethyl, propyl, methoxy, ethoxy,methyl-phenyl, NH₂, NH—(C₅-alkyl)-OH, —NHCH₃, —NH—CH₂CH₂(CH₃),—NHCH₂CH(CH₃)₂, —NH(C₄-alkyl)-OH, or —NH(C₄-alkyl). In anotherembodiment, R¹ is NH₂, —NH—(C₅-alkyl)-OH, —NH(C₄-alkyl), —NHCH₃, or—NHCH₂CH₂(CH₃).

In another embodiment, one of R³ or R⁶ is H, and the other may beC₁₋₆alkyl, such as methyl, ethyl, propyl, isopropyl, or butyl;C₁₋₆alkyl-aryl, such as benzyl, alpha-phenethyl, orbeta-phenmethyl-phenyl; C₁₋₆alkoxy, such as methoxy or ethoxy; aC₃₋₁₄cycloalkyl, such as cyclopropyl, cyclopentyl, or cyclohexyl; a 3-14membered cycloheteroalkyl, such as moprholinyl, tetrahydropyranyl,tetrahydrofuranyl, piperidinyl, or piperazinyl; a C₆₋₁₄aryl, such asphenyl; a 5-14 membered heteroaryl, such as pyridinyl, pyrazinyl, orpyrimidyl; or —C₁₋₆alkyl-O—R⁸, where R⁸ is H or C₁₋₆alkyl, (e.g.,—CH₂OH, —CH₂CH₂OH, —CH(CH₃)OH, —CH₂—O—CH₃, or —CH₂CH₂—O—CH₃). In anotherembodiment, one of R³ or R⁶ is H, and the other is hydroxymethylene,hydroxyethylene (e.g., 1-hydroxyethyl or 2-hydroxyethyl), hydroxypropyl(e.g., 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, or1-hydroxy-1-methylethyl), hydroxybutyl (e.g., 1-hydroxybutyl,2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl,1-hydroxy-1-methyl-propyl, 1-hydroxy-2,2-dimethyl-ethyl, or2-hydroxy-1,1-dimethyl-ethyl). In another embodiment, both R³ and R⁶ areH.

In another embodiment, R² is C₁₋₆alkyl, such as methyl, ethyl, propyl,or butyl; C₂₋₆alkenyl, ethenyl, propenyl; C₂₋₆alkynyl, a C₆₋₁₄arylgroup, such as phenyl; a C₃₋₁₄cycloalkyl group, such as cyclopropyl,cyclopentyl, or cyclohexyl; C₁₋₆alkoxy, such methoxy, or ethoxy;C₂₋₆-alkenyloxy, C₂₋₆-alkynyloxy, —C₁₋₆alkyl-O—R²⁷, where R²⁷ is H orC₁₋₆alkyl (e.g., —CH₂—O—CH₃, or —CH₂CH₂—O—CH₃, or CH₂CH₂—O—CH₂CH₃);C₁₋₆alkyl-C₃₋₁₄cycloalkyl (e.g., CH₂-cyclopropyl, —CH₂-cyclobutyl,—CH₂-cyclopentyl, —CH₂-cyclohexyl, —CH₂CH₂-cyclopropyl,—CH₂CH₂-cyclobutyl, —CH₂CH₂-cyclopentyl, or —CH₂CH₂-cyclohexyl);—C₁₋₆alkyl-O—C₀₋₆alkyl-C₆₋₁₄aryl (e.g., —CH₂—O—CH₂-phenyl,—CH₂CH₂—O—CH₂-phenyl, —CH₂—O—CH₂CH₂-phenyl, or —CH₂CH₂—O—CH₂CH₂-phenyl);C₁₋₆alkyl-O—SiR⁸R⁹R¹⁰, where R⁸, R⁹, and R¹⁰ are each independently H,C₁₋₆alkyl, C₆₋₁₄aryl, or a C₃₋₁₄cycloalkyl; or C₁₋₆haloalkyl (e.g,trifluoromethyl).

In another embodiment, R² is methyl, ethyl, propyl, ethenyl, propenyl,phenyl, cyclopropyl, cyclopentyl, cyclohexyl, methoxy, —CH₂—O—CH₃,—CH₂CH₂—O—CH₃, —CH₂CH₂—O—CH₂CH₃, —CH₂-cyclopropyl, —CH₂-cyclobutyl,—CH₂-cyclopentyl, —CH₂-cyclohexyl, —CH₂CH₂-cyclopropyl,—CH₂CH₂-cyclobutyl, —CH₂CH₂-cyclopentyl, —CH₂CH₂-cyclohexyl,—CH₂—O—CH₂-phenyl, —CH₂CH₂—O—CH₂-phenyl, —CH₂—O—CH₂CH₂-phenyl,—CH₂CH₂—O—CH₂CH₂-phenyl, trifluoromethyl, or —C₁₋₆alkyl-O—SiR⁸R⁹R¹⁰,where R⁸, R⁹, and R¹⁰ are each independently H, methyl, ethyl, orpropyl, phenyl, cyclopropyl, cyclopentyl, or cyclohexyl.

In a further embodiment, R² is methyl, ethyl, propyl, phenyl,cyclopropyl, cyclopentyl, cyclohexyl, methoxy, —CH₂—O—CH₃,—CH₂-cyclopropyl, —CH₂-cyclobutyl, —CH₂-cyclopentyl, —CH₂-cyclohexyl,—CH₂CH₂-cyclopropyl, —CH₂CH₂-cyclobutyl, —CH₂CH₂-cyclopentyl,—CH₂CH₂-cyclohexyl, or —CH₂—O—CH₂-phenyl. In yet another embodiment, R²is methyl, ethyl, propyl, phenyl, cyclopropyl, methoxy, —CH₂—O—CH₃,—CH₂-cyclopropyl, —CH₂-cyclobutyl, —CH₂-cyclopentyl, —CH₂-cyclohexyl, or—CH₂CH₂-cyclopropyl. In yet another embodiment R² is —CH₂-cyclopropyl.

In another embodiment, R⁴ and R⁵ are each independently H, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, a C₆₋₁₄aryl, a C₃₋₁₄cycloalkyl, a 3- to14-membered cycloheteroalkyl, a 5- to 14-membered heteroaryl group,C₁₋₆alkoxy, OH, —C₁₋₆alkylNR¹¹R¹², —C₁₋₆alkyl-O—R¹³, C₁₋₆alkyl-5- to14-membered heteroaryl group containing 1 to 3 heteroatoms eachindependently selected from O, N or S, or C(O)—C₁₋₆alkyl, wherein R⁴ orR⁵ may be unsubstituted or substituted by substituents as iteratedbelow.

In an embodiment, R¹¹, R¹², and R¹³ are each independently H, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, a C₆₋₁₄ aryl, a C₃₋₁₄ cycloalkyl group, a 3-to 14-membered cycloheteroalkyl containing 1 to 3 heteroatoms eachindependently selected from O, N or S, or a 5-14 membered heteroarylcontaining 1 to 3 heteroatoms each independently selected from O, N orS.

In another embodiment, the present invention includes compounds ofFormula (I) where R⁴ and R⁵ are each independently H, a C₆₋₁₄aryl,C₃₋₁₄cycloalkyl, a 3- to 14-membered cycloheteroalkyl containing 1 to 3heteroatoms each independently selected from O, N or S, or a 5-14membered heteroaryl containing 1 to 3 heteroatoms each independentlyselected from O, N or S, wherein said C₆₋₁₄aryl, C₃₋₁₄cycloalkyl, 3- to14-membered cycloheteroalkyl, or 5- to 14-membered heteroaryl isoptionally mono- or di-substituted by substituents selected from thegroup consisting of halogen, OH, C₁₋₆alkyl, C₁₋₆haloalkyl, —C₁₋₆alkylOH,C₁₋₆alkoxy, —NR¹⁴R¹⁵, —C(O)ONR¹⁶R¹⁷, —NR¹⁸C(O)R¹⁹, —NR²⁰C(O)OOR²¹,—C(O)R²², —C(O)OR²³, and —NR²⁴SO₂R²⁵.

In another embodiment, R⁴ is H, and R⁵ is methyl, ethyl, propyl, phenyl,cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, pyrrolidinyl,tetrahydropyranyl, pyridinyl, pyrimidinyl, or pyridazinyl; each of whichmay be unsubstituted or substituted with one or more of halogen, a 5- to14 membered heteroaryl (preferably, pyridinyl); OH, C₁₋₆alkyl(preferably C₁₋₄alkyl; C₁₋₆haloalkyl (preferably, trifluoromethyl),C₁₋₆alkylOR²⁷, C₁₋₆alkoxy (preferably, methoxy, or ethoxy), —NR¹⁴R¹⁵,—C(O)NR¹⁶R¹⁷, —NR¹⁸C(O)R¹⁹, —NR²⁰C(O)OR²¹, —C(O)R²², —C(O)OR²³, —CN,—SO₂R²⁶, —O—, or —NR²⁴SO₂R²⁵.

In an embodiment, R²³, R²⁴, R²⁵, R²⁶, and R²⁷ are each independently H,C₁₋₆alkyl (preferably, C₁₋₄alkyl), C₂₋₆alkenyl, C₂₋₆alkynyl, a C₆₋₁₄aryl (preferably, phenyl) C₃₋₁₄ cycloalkyl (preferably, cyclopropyl,cyclopentyl, or cyclohexyl) 3- to 14-membered cycloheteroalkylcontaining 1 to 3 heteroatoms each independently selected from O, N orS, or 5- to 14-membered heteroaryl containing 1 to 3 heteroatoms eachindependently selected from O, N or S.

In yet another embodiment, one of R⁴ or R⁵ is H, and the other is amoiety selected from methyl, ethyl, propyl, phenyl, cyclopentyl,cyclohexyl, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydropyranyl,pyridinyl, pyrimidinyl, or pyridazinyl; wherein said moiety isoptionally with one to two substitutents each independently selectedfrom the group consisting of F, Cl, pyridinyl, OH, methyl, ethyl,trifluoromethyl, 1-hydroxyethyl, 2-hydroxyethyl, —C(O)OH,—NHC(O)O-isopropyl, —NH₂, —NHSO₂CH₃, —SO₂CH₃, —CN, or —NHC(O)CH₃. Inanother embodiment, R⁴ is H, and R⁵ is methyl, ethyl, phenyl, orpiperidinyl, wherein said methyl, said ethyl, said phenyl and saidpiperidinyl groups are optionally substituted with one or moresubstitutents each independently selected from —OH, —CN, Cl, or F.

In another embodiment, one of R⁴ and R⁵ is H, and the other is phenyl orpyridinyl, wherein said phenyl and said pyridinyl are optionallysubstituted with one or more substitutents selected from F, Cl, OH,methyl, ethyl, CN, or CF₃.

In another embodiment, the present invention includes compounds ofFormula II:

or a pharmaceutically acceptable salt thereof, wherein

-   -   R¹ is (C₁-C₆)alkyl, —OCH₃, —NH₂, —NH(C₁-C₆)alkyl,        —NHCH₂(phenyl), —NHCH₂CH₂OH, —NHCH₂CH(OH)CH₃, —NHCH(CH₃)CH₂OH,        —NHCH₂CH(CH₃)₂OH, —NHCH₂CH₂OCH₃, —NH(C₃-C₆)cycloalkyl,        phenethylamino-, tetrahydropyranylamino-, or —SCH₃;    -   R² is (C₁-C₆)alkyl, —CF₃, —CH₂(cyclopropyl), —CH₂OH, or        —CH₂OCH₂(phenyl);    -   R⁴ is H; and    -   R⁵ is    -   (i) —(CH₂)_(n)—R^(5a), where n is 0, 1 or 2 and R^(5a) is        pyridinyl, 6-methoxypyridin-3-yl, furanyl, imidazolyl,        isoxazolyl, thiazolyl, thiadiazolyl, quinolinyl, 1H-indolyl,        benzo[d][1,3]dioxolyl, morpholinyl, tetrahydropyranyl, or        piperidinyl, where said chemical moiety is optionally        substituted with a methyl or halo; or    -   (ii) (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, or phenyl, wherein said        (C₁-C₆)alkyl, said (C₃-C₆)cycloalkyl, and said phenyl are        optionally substituted with one to two substituents each        independently selected from F, Cl, —CH₃, —CN, —OH, —OCH₃,        —NHC(O)—(C₁-C₄)alkyl, —NH₂, —N(CH₃)₂, —NHSO₂CH₃, —C(O)CH₃,        —C(O)OH, or —SO₂CH₃.

In one embodiment of the invention R⁵ is (i). In another embodiment—(CH₂)_(n)—R^(5a) wherein n is 0 or 1. In another embodiment n is 0.

In another embodiment R⁵ is (ii).

In another embodiment, the present invention includes a method ofinhibiting Vps34 activity in a subject, wherein the method comprisesadministering to the subject a therapeutically effective amount of thecompound of formula (I) or its prodrug or pharmaceutical compositioncomprising the compound of formula I or its prodrug and pharmaceuticallyacceptable excipients to a subject in need thereof.

In an embodiment, disease, disorder, or syndrome is hyperproliferativein a subject, wherein said subject is an animal including humans, andthe disease or disorder is selected from a group comprising cancer andinflammation. In another embodiment, the present invention includes thecompound of formula (I) for use in therapy.

In another embodiment, the present invention includes a pharmaceuticalcomposition comprising a compound of formula I and a pharmaceuticallyacceptable carrier or excipient. In another embodiment, the presentinvention includes a pharmaceutical composition comprising a compound offormula I in combination with a second active agent, and apharmaceutically acceptable carrier or excipient.

In yet another embodiment, the present invention includes a method oftreating a mammal comprising administration of a Vps34 inhibitor. In anembodiment, the invention includes administration of a Vps34 inhibitor,where the Vps34 inhibitor is a compound of formula I.

In still another embodiment of the present invention, the compound is astereoisomer or a tautomer.

Representative compounds of the invention include:

-   (1r,4r)-4-(2′-amino-4′-(cyclopropylmethyl)-4,5′-bipyrimidin-2-ylamino)cyclohexanol;-   (1r,4r)-4-(4′-(cyclopropylmethyl)-2′-(methylamino)-4,5′-bipyrimidin-2-ylamino)cyclohexanol;-   4-(4′-(cyclopropylmethyl)-4,5′-bipyrimidin-2-ylamino)cyclohexanol;-   N²-cyclohexyl-4′-(cyclopropylmethyl)-N^(2′)-methyl-4,5′-bipyrimidine-2,2′-diamine;-   4′-(cyclopropylmethyl)-N^(2′)-methyl-N²-(1-methylpiperidin-4-yl)-4,5′-bipyrimidine-2,2′-diamine;-   N²-(3-aminopropyl)-4′-(cyclopropylmethyl)-N^(2′)-methyl-4,5′-bipyrimidine-2,2′-diamine;-   4′-(cyclopropylmethyl)-N²-(3,5-dimethoxyphenyl)-N^(2′)-methyl-4,5′-bipyrimidine-2,2′-diamine;-   4′-(cyclopropylmethyl)-N²-(3,4-dimethoxyphenyl)-N^(2′)-methyl-4,5′-bipyrimidine-2,2′-diamine;-   4′-(cyclopropylmethyl)-N²-(6-methoxypyridin-3-yl)-N^(2′)-methyl-4,5′-bipyrimidine-2,2′-diamine;-   4′-(cyclopropylmethyl)-N^(2′)-methyl-N²-phenyl-4,5′-bipyrimidine-2,2′-diamine;-   4′-(cyclopropylmethyl)-N^(2′)-methyl-N²-(pyridin-4-yl)-4,5′-bipyrimidine-2,2′-diamine;-   4′-(cyclopropylmethyl)-N^(2′)-methyl-N²-(quinolin-3-yl)-4,5′-bipyrimidine-2,2′-diamine;-   N²-cyclobutyl-4′-(cyclopropylmethyl)-N^(2′)-methyl-4,5′-bipyrimidine-2,2′-diamine;-   4′-(cyclopropylmethyl)-N^(2′)-methyl-N²-(tetrahydro-2H-pyran-4-yl)-4,5′-bipyrimidine-2,2′-diamine;    N²-cyclopentyl-4′-(cyclopropylmethyl)-N²-methyl-4,5′-bipyrimidine-2,2′-diamine;-   tert-butyl    (1r,4r)-4-(4′-(cyclopropylmethyl)-2′-(methylamino)-4,5′-bipyrimidin-2-ylamino)cyclohexylcarbamate;-   N²-(4-aminocyclohexyl)-4′-(cyclopropylmethyl)-N^(2′)-methyl-4,5′-bipyrimidine-2,2′-diamine;-   4′-(cyclopropylmethyl)-N^(2′)-methyl-N²-(pyridin-3-yl)-4,5′-bipyrimidine-2,2′-diamine;-   4′-(cyclopropylmethyl)-N²-(4-methoxyphenyl)-N^(2′)-methyl-4,5′-bipyrimidine-2,2′-diamine;-   (1r,4r)-4-(4′-(cyclopropylmethyl)-2′-(methylamino)-4,5′-bipyrimidin-2-ylamino)cyclohexanecarboxylic    acid;-   4′-(cyclopropylmethyl)-N²-((1r,4r)-4-methoxycyclohexyl)-N^(2′)-methyl-4,5′-bipyrimidine-2,2′-diamine;-   (1r,4r)-4-(4′-(cyclopropylmethyl)-2′-ethyl-4,5′-bipyrimidin-2-ylamino)cyclohexanol;-   4-(4′-(cyclopropylmethyl)-2′-(methylamino)-4,5′-bipyrimidin-2-ylamino)cyclohexanol;-   (1r,4r)-4-(4′-(cyclopropylmethyl)-2′-methyl-4,5′-bipyrimidin-2-ylamino)cyclohexanol;-   4-(4′-(cyclopropylmethyl)-2′-methoxy-4,5′-bipyrimidin-2-ylamino)cyclohexanol;-   4′-(cyclopropylmethyl)-2′-methoxy-N-(pyridin-4-yl)-4,5′-bipyrimidin-2-amine;-   4′-(cyclopropylmethyl)-N²-(pyridin-4-yl)-4,5′-bipyrimidine-2,2′-diamine;-   4′-(cyclopropylmethyl)-2′-(methylthio)-N-(pyridin-4-yl)-4,5′-bipyrimidin-2-amine;-   N^(2′)-cyclopropyl-4′-(cyclopropylmethyl)-N²-(pyridin-4-yl)-4,5′-bipyrimidine-2,2′-diamine;-   4′-(cyclopropylmethyl)-N^(2′)-isopropyl-N²-(pyridin-4-yl)-4,5′-bipyrimidine-2,2′-diamine;-   N^(2′)-cyclohexyl-4′-(cyclopropylmethyl)-N²-(pyridin-4-yl)-4,5′-bipyrimidine-2,2′-diamine;-   N^(2′)-benzyl-4′-(cyclopropylmethyl)-N²-(pyridin-4-yl)-4,5′-bipyrimidine-2,2′-diamine;-   4′-(cyclopropylmethyl)-N^(2′)-isobutyl-N²-(pyridin-4-yl)-4,5′-bipyrimidine-2,2′-diamine;-   N^(2′)-cyclopentyl-4′-(cyclopropylmethyl)-N²-(pyridin-4-yl)-4,5′-bipyrimidine-2,2′-diamine;-   N^(2′)-cyclobutyl-4′-(cyclopropylmethyl)-N²-(pyridin-4-yl)-4,5′-bipyrimidine-2,2′-diamine;-   4′-(cyclopropylmethyl)-N²-(pyridin-4-yl)-N^(2′)-(tetrahydro-2H-pyran-4-yl)-4,5′-bipyrimidine-2,2′-diamine;-   (R)-4′-(cyclopropylmethyl)-N^(2′)-(1-phenylethyl)-N²-(pyridin-4-yl)-4,5′-bipyrimidine-2,2′-diamine;    N^(2′)-tert-butyl-4′-(cyclopropylmethyl)-N²-(pyridin-4-yl)-4,5′-bipyrimidine-2,2′-diamine;-   1-(4′-(cyclopropylmethyl)-2-(pyridin-4-ylamino)-4,5′-bipyrimidin-2′-ylamino)propan-2-ol;-   4′-(cyclopropylmethyl)-N^(2′)-(2-methoxyethyl)-N²-(pyridin-4-yl)-4,5′-bipyrimidine-2,2′-diamine;-   2-(4′-(cyclopropylmethyl)-2-(pyridin-4-ylamino)-4,5′-bipyrimidin-2′-ylamino)propan-1-ol;-   4′-(cyclopropylmethyl)-N^(2′)-neopentyl-N²-(pyridin-4-yl)-4,5′-bipyrimidine-2,2′-diamine;-   N^(2′)-sec-butyl-4′-(cyclopropylmethyl)-N²-(pyridin-4-yl)-4,5′-bipyrimidine-2,2′-diamine;-   4′-(cyclopropylmethyl)-N^(2′)-ethyl-N²-(pyridin-4-yl)-4,5′-bipyrimidine-2,2′-diamine;-   4′-(benzyloxymethyl)-N²-(pyridin-4-yl)-4,5′-bipyrimidine-2,2′-diamine;-   (2′-amino-2-(pyridin-4-ylamino)-4,5′-bipyrimidin-4′-yl)methanol;-   4′-(cyclopropylmethyl)-N²-(tetrahydro-2H-pyran-3-yl)-4,5′-bipyrimidine-2,2′-diamine;-   4′-(cyclopropylmethyl)-N²-(piperidin-4-yl)-4,5′-bipyrimidine-2,2′-diamine;-   N-((1r,4r)-4-(2′-amino-4′-(cyclopropylmethyl)-4,5′-bipyrimidin-2-ylamino)cyclohexyl)acetamide;-   N-((1r,4r)-4-(2′-amino-4′-(cyclopropylmethyl)-4,5′-bipyrimidin-2-ylamino)cyclohexyl)methanesulfonamide;-   2-(4′-(cyclopropylmethyl)-2-(pyridin-4-ylamino)-4,5′-bipyrimidin-2′-ylamino)ethanol;-   1-(4′-(cyclopropylmethyl)-2-(pyridin-4-ylamino)-4,5′-bipyrimidin-2′-ylamino)-2-methylpropan-2-ol;-   (S)-1-(4′-(cyclopropylmethyl)-2-(pyridin-4-ylamino)-4,5′-bipyrimidin-2′-ylamino)propan-2-ol;-   (R)-2-(4′-(cyclopropylmethyl)-2-(pyridin-4-ylamino)-4,5′-bipyrimidin-2′-ylamino)propan-1-ol;-   (S)-2-(4′-(cyclopropylmethyl)-2-(pyridin-4-ylamino)-4,5′-bipyrimidin-2′-ylamino)propan-1-ol;-   1-(4′-(cyclopropylmethyl)-2-(pyridin-4-ylamino)-4,5′-bipyrimidin-2′-ylamino)propan-2-ol;-   4′-methyl-N²-(pyridin-4-yl)-4,5′-bipyrimidine-2,2′-diamine;-   N-((1r,4r)-4-(4′-(cyclopropylmethyl)-2′-(2-hydroxy-2-methylpropylamino)-4,5′-bipyrimidin-2-ylamino)cyclohexyl)methanesulfonamide;-   4′-(cyclopropylmethyl)-N²-(pyridin-2-yl)-4,5′-bipyrimidine-2,2′-diamine;-   3-(2′-amino-4′-(cyclopropylmethyl)-4,5′-bipyrimidin-2-ylamino)-2,2-dimethylpropan-1-ol;-   4′-(cyclopropylmethyl)-N²-(3-methylisoxazol-5-yl)-4,5′-bipyrimidine-2,2′-diamine;-   4′-(cyclopropylmethyl)-N²-(1,3,4-thiadiazol-2-yl)-4,5′-bipyrimidine-2,2′-diamine;-   4′-(cyclopropylmethyl)-N²-(4-fluorophenyl)-4,5′-bipyrimidine-2,2′-diamine;-   4′-(cyclopropylmethyl)-N²-(furan-2-ylmethyl)-4,5′-bipyrimidine-2,2′-diamine;-   4′-(cyclopropylmethyl)-N²-(1H-indol-5-yl)-4,5′-bipyrimidine-2,2′-diamine;-   N²-(benzo[d][1,3]dioxol-5-yl)-4′-(cyclopropylmethyl)-4,5′-bipyrimidine-2,2′-diamine;-   N²-(2-chloropyridin-4-yl)-4′-(cyclopropylmethyl)-4,5′-bipyrimidine-2,2′-diamine;-   N-(4-(2′-amino-4′-(cyclopropylmethyl)-4,5′-bipyrimidin-2-ylamino)phenyl)acetamide;-   N²-(4-chlorophenyl)-4′-(cyclopropylmethyl)-4,5′-bipyrimidine-2,2′-diamine;-   N²-(2-(1H-indol-3-yl)ethyl)-4′-(cyclopropylmethyl)-4,5′-bipyrimidine-2,2′-diamine;-   4′-(cyclopropylmethyl)-N²-(pyridin-3-ylmethyl)-4,5′-bipyrimidine-2,2′-diamine;-   4′-(cyclopropylmethyl)-N²-(2-morpholinoethyl)-4,5′-bipyrimidine-2,2′-diamine;-   N²-(2-(1H-imidazol-4-yl)ethyl)-4′-(cyclopropylmethyl)-4,5′-bipyrimidine-2,2′-diamine;-   N²-(4-aminophenyl)-4′-(cyclopropylmethyl)-4,5′-bipyrimidine-2,2′-diamine;-   N²-(5-chloropyridin-2-yl)-4′-(cyclopropylmethyl)-4,5′-bipyrimidine-2,2′-diamine;-   4′-(cyclopropylmethyl)-N²-(2-methyl-1H-indol-5-yl)-4,5′-bipyrimidine-2,2′-diamine;-   4-(2′-amino-4′-(cyclopropylmethyl)-4,5′-bipyrimidin-2-ylamino)benzonitrile;-   4′-(cyclopropylmethyl)-N²-(3-(dimethylamino)phenyl)-4,5′-bipyrimidine-2,2′-diamine;-   4′-(cyclopropylmethyl)-N-(pyridin-4-yl)-4,5′-bipyrimidin-2-amine;-   N²-(4-fluorophenyl)-4′-methyl-4,5′-bipyrimidine-2,2′-diamine;-   N²-(4-fluorophenyl)-4,5′-bipyrimidine-2,2′-diamine;-   1-(2-(2-chloropyridin-4-ylamino)-4′-(cyclopropylmethyl)-4,5′-bipyrimidin-2′-ylamino)-2-methylpropan-2-ol;-   4-(4′-(cyclopropylmethyl)-2′-(2-hydroxy-2-methylpropylamino)-4,5′-bipyrimidin-2-ylamino)benzonitrile;-   1-(4′-(cyclopropylmethyl)-2-(4-fluorophenylamino)-4,5′-bipyrimidin-2′-ylamino)-2-methylpropan-2-ol;-   1-(4′-(cyclopropylmethyl)-2-(4-(methylsulfonyl)phenylamino)-4,5′-bipyrimidin-2′-ylamino)-2-methylpropan-2-ol;-   1-(2-(4-chlorophenylamino)-4′-(cyclopropylmethyl)-4,5′-bipyrimidin-2′-ylamino)-2-methylpropan-2-ol;-   N-(4-(4′-(cyclopropylmethyl)-2′-(2-hydroxy-2-methylpropylamino)-4,5′-bipyrimidin-2-ylamino)phenyl)acetamide;-   2-methyl-1-(2-(pyridin-4-ylamino)-4′-(trifluoromethyl)-4,5′-bipyrimidin-2′-ylamino)propan-2-ol;-   N²-(pyridin-4-yl)-4′-(trifluoromethyl)-4,5′-bipyrimidine-2,2′-diamine;-   4-(2′-(2-hydroxy-2-methylpropylamino)-4′-(trifluoromethyl)-4,5′-bipyrimidin-2-ylamino)benzonitrile;-   4-(4′-ethyl-2′-(2-hydroxy-2-methylpropylamino)-4,5′-bipyrimidin-2-ylamino)benzonitrile;    and-   4-(2′-(2-hydroxy-2-methylpropylamino)-4′-phenyl-4,5′-bipyrimidin-2-ylamino)benzonitrile.

DEFINITIONS

As used herein, “alkyl” or “alkylene” refers to a straight chain orbranched hydrocarbon from 1 to 20 carbon atoms. Alkyl moieties havingfrom 1 to 5 carbons are referred to as “lower alkyl” and examplesinclude, but are not limited to, methyl, ethyl, n-propyl, isopropyl,n-butyl, t-butyl, isobutyl, n-pentyl, iso-pentyl, neopentyl and.

“C₁₋₆-haloalkyl” refers to an alkyl group substituted by up to sevenhalogen groups, e.g. fluoro groups. For example, where the substituentis fluoro, common haloalkyl groups are trifluoroalkyl,2,2,2-trifluoroethyl or 2,2,2,1,1-pentafluoroethyl groups.

The term “alkenyl” refers to a monovalent group derived from ahydrocarbon having at least one carbon-carbon double bond. The term“C₂-C₆-alkenyl” refers to a monovalent group derived from a hydrocarbonhaving two to six carbon atoms and comprising at least one carbon-carbondouble bond.

The term “alkynyl” refers to a monovalent group derived from ahydrocarbon having at least one carbon-carbon triple bond. The term“C₂-C₆-alkynyl” refers to a monovalent group derived from a hydrocarbonhaving two to six carbon atoms and comprising at least one carbon-carbontriple bond.

The term “alkoxy” refers to a group in which an alkyl group is attachedto oxygen, wherein alkyl is as previously defined.

“Cycloalkyl” or “cycloalkylene” refers to a 3-14 membered monocyclic orbicyclic carbocyclic ring, The cycloalkyl or cycloalklene may optionallyinclude one to three ring members selected from —C(═O), —N(R²⁹)q-, —O—and S(O)r where R²⁹ is H or C₁₋₆-alkyl, q is 0-1 and r is 0-2. Thecycloalkyl may be attached using any of the ring members. Suitablecycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl or cyclooctyl.

“Aryl” or “arylene” represents a 6-14 membered single or fused ringsystem, wherein at least one of the fused rings is aromatic and theother ring is another aromatic ring or a saturated or partiallyunsaturated cycloalkyl. The aryl may be attached using any of the ringmembers. Suitable aryl groups include phenyl, naphthyl, anthracyl andphenanthryl.

“Heteroaryl” or “heteroarylene” refers to a 5-14 membered monocyclic orfused ring system, wherein the monocyclic and at least one of thebicyclic fused rings is an aromatic ring comprising either (a) 1 to 4nitrogen atoms, (b) one oxygen or one sulphur atom or (c) 1 oxygen atomor 1 sulphur atom and 1 or 2 nitrogen atoms, and the fused ring may bean aryl group, another heteroaryl, a saturated or partially unsaturatedcycloalkyl, or a saturated or partially unsaturated heterocycle. Theheteroaryl may optionally include one to three ring members selectedfrom the group consisting of —C(O), —N(R³¹)q-, —O— and S(O)r where R³¹is H or C₁₋₆-alkyl, q is 0-1 and r is 0-2. The heteroaryl may beattached using any of the ring members. Suitable monocyclic heteroarylgroups include pyridyl, thienyl, furanyl, pyrrolyl, pyrazolyl,imidazoyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl,oxadiazolyl, thiadiazolyl and tetrazolyl. Suitable fused heteroarylgroups include indolyl, benzofuranyl, quinolyl, isoquinolyl indazolyl,indolinyl, isoindolyl, indolizinyl, benzamidazolyl, and quinolinyl

“Cycloheteroalkyl” or “cycloheteroalkylene” or “heterocycle” refers to a3-14 membered nonaromatic rings that are either partially or fullyhydrogenated and may exist as a single ring, bicyclic ring or a spiralring comprising one or two ring members selected from the groupconsisting of —N(R³²)—, —O— and —S(O)_(r)—. The cycloheteroalkyl mayoptionally include one to three ring members selected from —C(═O),—N(R³³)q-, —O— and S(O)r where R³² or R³³ is H or C₁₋₆-alkyl, q is 0-1and r is 0-2. The cycloheteroalkyl may be attached using any of the ringmembers. Suitable heterocycloalkyl groups include [1,3]dioxolane,[1,4]dioxane, oxiranyl, aziridinyl, oxetanyl, azetidinyl,tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl,morpholino, thiomorpholinyl, piperazinyl, azepinyl, oxapinyl, oxazepinyland diazepinyl.

“Halogen” or “halo” may be fluorine, chlorine, bromine or iodine.

It is to be understood that the terminology C(O) refers to a —C═O group,whether it be ketone, aldehyde or acid or acid derivative. Similarly,S(O) refers to a —S═O group.

The phrase “therapeutically effective amount” means an amount of acompound of the present invention that (i) treats or prevents theparticular disease, condition, or disorder, (ii) attenuates,ameliorates, or eliminates one or more symptoms of the particulardisease, condition, or disorder, or (iii) prevents or delays the onsetof one or more symptoms of the particular disease, condition, ordisorder described herein.

The term “animal” refers to humans (male or female), companion animals(e.g., dogs, cats and horses), food-source animals, zoo animals, marineanimals, birds and other similar animal species. “Edible animals” refersto food-source animals such as cows, pigs, sheep and poultry.

The phrase “pharmaceutically acceptable” indicates that the substance orcomposition must be compatible chemically and/or toxicologically, withthe other ingredients comprising a formulation, and/or the mammal beingtreated therewith.

The terms “treating”, “treat”, or “treatment” embrace both preventative,i.e., prophylactic, and palliative treatment.

The term “compounds of the present invention” (unless specificallyidentified otherwise) refer to compounds of Formula (I), prodrugsthereof, pharmaceutically acceptable salts of the compounds, and/orprodrugs, and hydrates or solvates of the compounds, salts, and/orprodrugs, as well as, all stereoisomers (including diastereoisomers andenantiomers), tautomers and isotopically labeled compounds.

DETAILED DESCRIPTION

The present invention provides compounds and pharmaceutical formulationsthereof that are useful in the treatment of diseases, conditions and/ordisorders modulated by the inhibition of Vps34.

Compounds of the present invention may be synthesized by syntheticroutes that include processes analogous to those well-known in thechemical arts, particularly in light of the description containedherein. The starting materials are generally available from commercialsources such as Aldrich Chemicals (Milwaukee, Wis.) or are readilyprepared using methods well known to those skilled in the art (e.g.,prepared by methods generally described in Louis F. Fieser and MaryFieser, Reagents for Organic Synthesis, v. 1-19, Wiley, New York(1967-1999 ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl.ed. Springer-Verlag, Berlin, including supplements (also available viathe Beilstein online database)).

For illustrative purposes, the reaction schemes depicted below providepotential routes for synthesizing the compounds of the present inventionas well as key intermediates. For a more detailed description of theindividual reaction steps, see the Examples section below. Those skilledin the art will appreciate that other synthetic routes may be used tosynthesize the inventive compounds. Although specific starting materialsand reagents are depicted in the schemes and discussed below, otherstarting materials and reagents can be easily substituted to provide avariety of derivatives and/or reaction conditions. In addition, many ofthe compounds prepared by the methods described below can be furthermodified in light of this disclosure using conventional chemistry wellknown to those skilled in the art.

Compounds of Formula I where G³ is C—H, and G⁴ and G⁵ are both nitrogencan be prepared using the synthesis outlined below in Scheme I.

Generally, the compounds of formula I-A can be prepared according toScheme 1, which contains five steps. As to the individual steps in thescheme above, step 1 involves the alkylation of commercially available4-methyl-2-(methylthio)pyrimidine with R2 substituted Weinreb amides, oralternatively R2-substituted benzyl esters. Further reaction of ketonesof formula 2 with N,N-dimethylformamide dimethyl acetal in the absenceof solvent at 80° C. affords vinylogous amides 3. Intermediates of theformula 4a-f are prepared by cyclization of intermediate 3 withR-substituted guanidines at 120° C. in the presence of a base such aspotassium carbonate. In step 4, the sulfide is converted to thesulfoxide or sulfone by reaction with a suitable oxidizing agent, suchas m-Chloroperoxybenzoic acid. Conversion to final compounds I-A can beaccomplished by reaction of intermediates 5 with aliphatic amines in themicrowave at 160° C. or by addition of deprotonated aryl orheteroarylamines.

Generally, the compounds of formula II-A can be prepared according toScheme 2, starting from intermediate 2, which is prepared as describedin Scheme 1. As to the individual steps in the scheme above, step 1involves the oxidation of the sulfide to the sulfone or sulfoxideutilizing a suitable oxidizing agent such as m-Chloroperoxybenzoic acid.The sulfoxide or sulfone moiety can then be displaced by reaction withaliphatic amines in the microwave at 160° C. or alternatively byaddition of deprotonated aryl or heteroarylamines. Further reaction ofketones of formula 8 with N,N-dimethylformamide dimethyl acetal in theabsence of solvent at 80° C. affords vinylogous amides 9. Compounds II-Acan be prepared from intermediate 9 via reaction with2-methyl-2-thiopseudourea sulfate in the presence of a suitable basesuch as potassium carbonate at 120° C. followed by reaction ofintermediate 11 with R substituted amines in the microwave at 160° C.Alternatively, Compounds I-A can be prepared from intermediate 9 byheating with R substituted guanidines.

Scheme III below describes an alternative synthesis for preparingCompounds of Formula III-A

Generally, the compounds of formula III-A can be prepared according toScheme 3, starting from 5-acetyl-2-amino-4-methylpyrimidine (Alfa Aesar)and heating in N,N-dimethylformamide dimethyl acetal, followed byreaction with substituted guanidines in the presence of a suitable basesuch as potassium carbonate at 120° C.

Scheme IV below describes the synthesis for preparing compounds of theformula IV-A.

Generally, the compounds of formula 1V-A can be prepared according toscheme 4, utilizing a Suzuki coupling with the appropriate boronateester and 2,4-dichloropyrimidine. Subsequent reaction with variousamines in the microwave affords the desired aminopyrimidines.

Scheme V below describes and alternate synthesis of the compounds offormula I-A, or V-A.

Generally, the compounds of formula V-A can be prepared according toScheme 5, starting from 5-acetyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one(Ryan Scientific). Step 1 involves methylation, which is followed byreaction with N,N-dimethylformamide dimethyl acetal at 120° C. andsubsequent reaction with substituted guanidines in the presence of asuitable base such as potassium carbonate at 120° C. Final compounds areprepared by chlorination with a reagent such as POCl₃ followed byreaction with various amines at 200° C. in the microwave.

The compounds of the present invention may be isolated and used per seor in the form of its pharmaceutically acceptable salt, solvate and/orhydrate. Many of the compounds represented by Formula I are capable offorming acid addition salts, particularly pharmaceutically acceptableacid addition salts. Pharmaceutically acceptable acid addition salts ofthe compound of the present invention include those of inorganic acids,for example, hydrohalic acids such as hydrochloric acid, hydrobromicacid or hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid;and organic acids, for example aliphatic monocarboxylic acids such asformic acid, acetic acid, propionic acid and butyric acid, aliphatichydroxy acids such as lactic acid, citric acid, tartaric acid or malicacid, dicarboxylic acids such as maleic acid or succinic acid, aromaticcarboxylic acids such as benzoic acid, p-chlorobenzoic acid,diphenylacetic acid or triphenylacetic acid, aromatic hydroxy acids suchas o-hydroxybenzoic acid, p-hydroxybenzoic acid,1-hydroxynaphthalene-2-carboxylic acid or3-hydroxynaphthalene-2-carboxylic acid, and sulfonic acids such asmethanesulfonic acid or benzenesulfonic acid. These salts may beprepared from compounds of formula I and Id by known salt-formingprocedures.

Compounds of the present invention which contain acidic, e.g. carboxyl,groups, are also capable of forming salts with bases, in particularpharmaceutically acceptable bases such as those well known in the art;suitable such salts include metal salts, particularly alkali metal oralkaline earth metal salts such as sodium, potassium, magnesium orcalcium salts, or salts with ammonia or pharmaceutically acceptableorganic amines or heterocyclic bases such as ethanolamines, benzylaminesor pyridine. These salts may be prepared from compounds of Formula I byknown salt-forming procedures.

For those compounds containing an asymmetric carbon atom, the compoundsexist in individual optically active isomeric forms or as mixturesthereof, e.g. as racemic or diastereomeric mixtures. The presentinvention embraces both individual optically active R and S isomers aswell as mixtures, e.g. racemic or diastereomeric mixtures, thereof. Inaddition, the present invention embraces all geometric and positionalisomers. For example, if a compound of the present inventionincorporates a double bond or a fused ring, both the cis- andtrans-forms, as well as mixtures, are embraced within the scope of theinvention.

Diastereomeric mixtures can be separated into their individualdiastereoisomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereoisomers and converting (e.g., hydrolyzing) theindividual diastereoisomers to the corresponding pure enantiomers. Also,some of the compounds of the present invention may be atropisomers(e.g., substituted biaryls) and are considered as part of thisinvention. Enantiomers can also be separated by use of a commerciallyavailable chiral HPLC column.

The compounds of the present invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms. For purposes of the presentinvention, solvates (including hydrates) are considered pharmaceuticalcompositions, e.g., a compound of Formula I (or pharmaceuticallyacceptable salt thereof) in combination with an excipient, wherein theexcipient is a solvent.

It is also possible that the intermediates and compounds of the presentinvention may exist in different tautomeric forms, and all such formsare embraced within the scope of the invention. The term “tautomer” or“tautomeric form” refers to structural isomers of different energieswhich are interconvertible via a low energy barrier. For example, protontautomers (also known as prototropic tautomers) include interconversionsvia migration of a proton, such as keto-enol and imine-enamineisomerizations. A specific example of a proton tautomer is the imidazolemoiety where the proton may migrate between the two ring nitrogens.Valence tautomers include interconversions by reorganization of some ofthe bonding electrons.

The present invention includes all pharmaceutically acceptableisotopically-labeled compounds of Formula (I) wherein one or more atomsare replaced by atoms having the same atomic number, but an atomic massor mass number different from the atomic mass or mass number usuallyfound in nature.

Examples of isotopes suitable for inclusion in the compounds of theinvention comprises isotopes of hydrogen, such as ²H and ³H, carbon,such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶Cl, fluorine, such as ¹⁸F,iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as ¹³N and ¹⁵N, oxygen,such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P, and sulphur, such as³⁵S.

Substitution with heavier isotopes such as deuterium, i.e. ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances.

Isotopically-labeled compounds of formula (I) can generally be preparedby conventional techniques known to those skilled in the art or byprocesses analogous to those described in the accompanying Examples andPreparations Sections using an appropriate isotopically-labeled reagentin place of the non-labeled reagent previously employed.

Compounds of the present invention are useful for treating diseases,conditions and disorders modulated by the inhibition of the Vps34enzyme; consequently, the compounds of the present invention (includingthe compositions and processes used therein) may be used in themanufacture of a medicament for the therapeutic applications describedherein. Hence, another embodiment of the present invention is apharmaceutical composition comprising a therapeutically effective amountof a compound of the present invention and a pharmaceutically acceptableexcipient, diluent or carrier.

A typical formulation is prepared by mixing a compound of the presentinvention and a carrier, diluent or excipient. Suitable carriers,diluents and excipients are well known to those skilled in the art andinclude materials such as carbohydrates, waxes, water soluble and/orswellable polymers, hydrophilic or hydrophobic materials, gelatin, oils,solvents, water, and the like. The particular carrier, diluent orexcipient used will depend upon the means and purpose for which thecompound of the present invention is being applied. Solvents aregenerally selected based on solvents recognized by persons skilled inthe art as safe (GRAS) to be administered to a mammal. In general, safesolvents are non-toxic aqueous solvents such as water and othernon-toxic solvents that are soluble or miscible in water. Suitableaqueous solvents include water, ethanol, propylene glycol, polyethyleneglycols (e.g., PEG400, PEG300), etc. and mixtures thereof. Theformulations may also include one or more buffers, stabilizing agents,surfactants, wetting agents, lubricating agents, emulsifiers, suspendingagents, preservatives, antioxidants, opaquing agents, glidants,processing aids, colorants, sweeteners, perfuming agents, flavoringagents and other known additives to provide an elegant presentation ofthe drug (i.e., a compound of the present invention or pharmaceuticalcomposition thereof) or aid in the manufacturing of the pharmaceuticalproduct (i.e., medicament).

The formulations may be prepared using conventional dissolution andmixing procedures. For example, the bulk drug substance (i.e., compoundof the present invention or stabilized form of the compound (e.g.,complex with a cyclodextrin derivative or other known complexationagent)) is dissolved in a suitable solvent in the presence of one ormore of the excipients. The compound of the present invention istypically formulated into pharmaceutical dosage forms to provide aneasily controllable dosage of the drug and to give the patient anelegant and easily handleable product.

The pharmaceutical composition (or formulation) for application may bepackaged in a variety of ways depending upon the method used foradministering the drug. Generally, an article for distribution includesa container having deposited therein the pharmaceutical formulation inan appropriate form. Suitable containers are well-known to those skilledin the art and include materials such as bottles (plastic and glass),sachets, ampoules, plastic bags, metal cylinders, and the like. Thecontainer may also include a tamper-proof assemblage to preventindiscreet access to the contents of the package. In addition, thecontainer has deposited thereon a label that describes the contents ofthe container. The label may also include appropriate warnings.

The compounds of the present invention are useful as both prophylacticand therapeutic treatments for diseases or conditions related to thehyperactivity of VPS34, as well as diseases or conditions modulated bythe autophagy and endocytic pathways.

Vps34 inhibitors can be used to inhibit autophagy in a variety ofdiseases, including but not limited to a variety of human cancersincluding colon/rectum, lung, breast, prostrate, urinary, kidney, andpancreatic. Other diseases where Vps34 can be used to modulate autophagyinclude neurodegenerative disorders such as HD, PD, ALS, inflammatorybowel disease (including Crohn's disease), malarial infection, anddengue.

Thus, as a further aspect, the invention relates to a method fortreating a disease or condition related to the hyperactivity of Vps34,or a disease or condition modulated by the Vps34, comprisingadministration of an effective therapeutic amount of a compound offormula (I) or a pharmaceutically acceptable salt thereof.

As a further aspect, the invention relates to a method for treatingproliferative diseases, such as cancer, comprising administration of aneffective amount of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof.

Examples of cancers include but are not limited to acute and chronicmyeloid leukemia, acute lymphoblastic leukemia, chronic lymphocyticleukemia, myeloproliferative diseases, multiple myeloma, myelodysplasticsyndrome, Hodgkin's disease, non-Hodgkin's lymphoma, malignant lymphoma,colorectal cancer, kidney, lung, liver, pancreatic, breast, glioma, orneuroblastoma.

Additionally, compounds of formula (I) may also be useful astherapeutics for diseases such as muscle diseases such as centralnuclear myopathies (e.g. X-linked myotubular myopathies),chloroquine-induced myopathy, myopathies with excessive autophagy,Duchene's muscular dystrophy, Charcot Marie Tooth Disease (e.g. type4B), demyelinating neuropathies, celiac disease, inflammatory boweldisease, Crohns' disease and various autoimmune diseases.

An Vps34 inhibitor of the present invention may be usefully combinedwith another pharmacologically active compound, or with two or moreother pharmacologically active compounds, particularly in the treatmentof cancer. For example, a compound of the formula (I), or apharmaceutically acceptable salt thereof, as defined above, may beadministered simultaneously, sequentially or separately in combinationwith one or more agents selected from, e.g., proteosome inhibitors,Bcl-2 inhibitors, Bcr-Abl inhibitors such as Gleevec and derivatives,mTOR inhibitors, PI3K inhibitors, dual PI3K-mTOR inhibitors, lipidkinase inhibitors, Ras, Raf, MEK, ERK1/2 inhibitors, TNF-R ligands,UPR/ER stress inducers, or other chemotherapeutic compounds. Further,alternatively or in addition they may be used in combination with othertumor treatment approaches, including surgery, ionizing radiation,photodynamic therapy, implants, e.g. with corticosteroids, hormones, orthey may be used as radiosensitizers. Also, in anti-inflammatory and/orantiproliferative treatment, combination with anti-inflammatory drugs isincluded. Combination is also possible with antihistamine drugsubstances, bronchodilatatory drugs, NSAID or antagonists of chemokinereceptors.

Compounds of the present invention may also be combined withdisease-modifying anti-rheumatic agents (DMARDs), e.g. methotrexate,leflunamide, sulfasalazine; gold salts, penicillamine,hydroxychloroquine and chloroquine.

The term “mTOR inhibitors” relates to compounds which inhibit themammalian target of rapamycin (mTOR) and which possess antiproliferativeactivity such as sirolimus (Rapamune), everolimus (CerticanÔ), CCI-779,RAD001, and ABT578. Other examples of mTOR inhibitors would include“catalytic” modulators such as NVP-BEZ235 and Ku-0063794.

The term “proteasome inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit the activity of the proteasome. Compoundswhich target, decrease or inhibit the activity of the proteasome includee.g. Bortezomid (Velcade) and MLN 341. The term “compoundstargeting/decreasing a protein or lipid kinase activity”; or a “proteinor lipid phosphatase activity”; or “further anti-angiogenic compounds”as used herein includes, but is not limited to, protein tyrosine kinaseand/or serine and/or threonine kinase inhibitors or lipid kinaseinhibitors, e.g.,

a) compounds targeting, decreasing or inhibiting the activity of theplatelet-derived growth factor-receptors (PDGFR), such as compoundswhich target, decrease or inhibit the activity of PDGFR, especiallycompounds which inhibit the PDGF receptor, e.g. aN-phenyl-2-pyrimidine-amine derivative, e.g. imatinib, SU101, SU6668 andGFB-111;

b) compounds targeting, decreasing or inhibiting the activity of thefibroblast growth factor-receptors (FGFR);

c) compounds targeting, decreasing or inhibiting the activity of theinsulin-like growth factor receptor I (IGF-IR), such as compounds whichtarget, decrease or inhibit the activity of IGF-IR, especially compoundswhich inhibit the kinase activity of IGF-I receptor, such as thosecompounds disclosed in WO 02/092599, or antibodies that target theextracellular domain of IGF-I receptor or its growth factors;

d) compounds targeting, decreasing or inhibiting the activity of the Trkreceptor tyrosine kinase family, or ephrin B4 inhibitors;

e) compounds targeting, decreasing or inhibiting the activity of the Ax1receptor tyrosine kinase family;

f) compounds targeting, decreasing or inhibiting the activity of the Retreceptor tyrosine kinase;

g) compounds targeting, decreasing or inhibiting the activity of theKit/SCFR receptor tyrosine kinase, i.e C-kit receptor tyrosinekinases—(part of the PDGFR family), such as compounds which target,decrease or inhibit the activity of the c-Kit receptor tyrosine kinasefamily, especially compounds which inhibit the c-Kit receptor, e.g.imatinib;

h) compounds targeting, decreasing or inhibiting the activity of membersof the c-Abl family, their gene-fusion products (e.g. BCR-Abl kinase)and mutants, such as com-pounds which target decrease or inhibit theactivity of c-AbI family members and their gene fusion products, e.g. aN-phenyl-2-pyrimidine-amine derivative, e.g. imatinib or nilotinib(AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; ordasatinib (BMS-354825)

i) compounds targeting, decreasing or inhibiting the activity of membersof the protein kinase C (PKC) and Raf family of serine/threoninekinases, members of the MEK, SRC, JAK, FAK, PDK1, PKB/Akt, and Ras/MAPKfamily members, and/or members of the cyclin-dependent kinase family(CDK) and are especially those staurosporine derivatives disclosed inU.S. Pat. No. 5,093,330, e.g. midostaurin; examples of further compoundsinclude e.g. UCN-01, safingol, BAY 43-9006, Bryostatin 1, Perifosine;Ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521;LY333531/LY379196; isochinoline compounds such as those disclosed in WO00/09495; FTIs; BEZ235 (a PI3K inhibitor) or AT7519 (CDK inhibitor);

j) compounds targeting, decreasing or inhibiting the activity ofprotein-tyrosine kinase inhibitors, such as compounds which target,decrease or inhibit the activity of protein-tyrosine kinase inhibitorsinclude imatinib mesylate (GLEEVEC) or tyrphostin. A tyrphostin ispreferably a low molecular weight (mw<1500) compound, or apharmaceutically acceptable salt thereof, especially a compound selectedfrom the benzylidenemalonitrile class or the S-arylbenzenemalonirile orbisubstrate quinoline class of compounds, more especially any compoundselected from the group consisting of Tyrphostin A23/RG-50810; AG 99;Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; TyrphostinB44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494;Tyrphostin AG 556, AG957 and adaphostin(4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester;NSC 680410, adaphostin);

k) compounds targeting, decreasing or inhibiting the activity of theepidermal growth factor family of receptor tyrosine kinases (EGFR,ErbB2, ErbB3, ErbB4 as homo- or heterodimers) and their mutants, such ascompounds which target, decrease or inhibit the activity of theepidermal growth factor receptor family are especially compounds,proteins or antibodies which inhibit members of the EGF receptortyrosine kinase family, e.g. EGF receptor, ErbB2, ErbB3 and ErbB4 orbind to EGF or EGF related ligands, and are in particular thosecompounds, proteins or monoclonal antibodies generically andspecifically disclosed in WO 97/02266, e.g. the compound of ex. 39, orin EP 0 564 409, WO 99/03854, EP 0520722, EP 0 566 226, EP 0 787 722, EP0 837 063, U.S. Pat. No. 5,747,498, WO 98/10767, WO 97/30034, WO97/49688, WO 97/38983 and, especially, WO 96/30347 (e.g. compound knownas CP 358774), WO 96/33980 (e.g. compound ZD 1839) and WO 95/03283 (e.g.compound ZM105180); e.g. trastuzumab (Herceptin), cetuximab (Erbitux),Iressa, Tarceva, OSI-774, CI-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5,E6.2, E6.4, E2.11, E6.3 or E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidinederivatives which are disclosed in WO 03/013541; and

l) compounds targeting, decreasing or inhibiting the activity of thec-Met receptor, such as compounds which target, decrease or inhibit theactivity of c-Met, especially compounds which inhibit the kinaseactivity of c-Met receptor, or antibodies that target the extracellulardomain of c-Met or bind to HGF.

“Other chemotherapeutic compounds” include, but are not limited to,plant alkaloids, hormonal compounds and antagonists; biological responsemodifiers, preferably lymphokines or interferons; antisenseoligonucleotides or oligonucleotide derivatives; shRNA or siRNA; ormiscellaneous compounds or compounds with other or unknown mechanism ofaction.

EXAMPLES

The abbreviations listed below have the corresponding meanings:

DCM: Dichloromethane

DME: Dimethyl ether

DMF: Dimethylformamide

DMF-DMA: N,N-Dimethylformamide dimethyl acetal

DMSO: Dimethylsulfoxide

EtOAc: Ethyl acetate

Fe(acac)₃: Ferric acetylanetonate

HCl: Hydrochloric acid

HPLC: High performance liquid chromatography

hr: Hour

HRMS: High resonance mass spectrometry

K₂CO₃: Potassium carbonate

LCMS: Liquid chromatography mass spectrometry

LHMDS: Lithium hexamethyldisilazide

LiHMDS: Lithium hexamethyldisilazide

mCPBA: m-Chloroperoxybenzoic acid

MeCN: Acetonitrile

MeI: Methyl iodide

MeOH: Methanol

Min: Minutes

MS: Mass spectrometry

MSCl: Methanesulfonyl chloride

NaOH: Sodium hydroxide

Na₂CO₃: Sodium carbonate

NMP: 1-Methyl-2-pyrrolidinone

PdCl₂.CH₂Cl₂:[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane

POCl₃: Phosphorus oxychloride

rt: Room temperature

TBAF: Tetrabutylammonium fluoride

THF: Tetrahydrofuran

TLC: Thin layer chromatography

Tol: Toluene

t_(R): Retention time

UV: Ultraviolet

μW: Microwave

Analytical HPLC Methods:

Method 1: Inertsil ODS3 100×3 mm C18 column at the flow rate of 1.0mL/min, with a gradient of 5-95% acetonitrile/water with 0.1% formicacid over 7.75 min

Method 2: Inertsil C₈₋₃ column with a gradient of 5-95%acetonitrile/water with 5 mM ammonium formate over 2.0 min

All HPLC retention times refer to Method 1 unless otherwise denoted by(*), which refers to Method 2.

Preparation of intermediate1-Cyclopropyl-3-[2-(methylsulfanyl)pyrimidin-4-yl]propan-2-one (2)

To a solution of 4-methyl-2-(methylthio)pyrimidine (5.63 mL, 40.4 mmol)in THF (20 mL) at −10° C., LiHMDS (60.6 mL, 60.6 mmol) (1N in MBTE) wasadded dropwise under nitrogen. The reaction mixture coagulated, andstopped stirring. For this, additional THF (40 mL) was added to dissolvethe highly viscous mixture. The reaction was warmed up to rt and wasstirred for 30 minutes. The reaction mixture was re-cooled to −10° C.,then 2-cyclopropyl-N-methoxy-N-methylacetamide (7.47 g, 40.4 mmol) wasadded dropwise. The reaction mixture was warmed up to rt, then stirredfor an additional 2 hours. The reaction was partitioned between ammoniumchloride solution and EtOAc. The organic layer was separated, and theaqueous layer was back-extracted. The organic extracts were combined,washed with brine, dried over sodium sulfate, then concentrated invacuo. The crude product was purified by Biotage™ silica gelchromatography [100 g SNAP column, 10% EtOAc/heptane to 100% EtOAc] toobtain the desired product, which was still contaminated significantlywith the starting material, 4-methyl-2-(methylthio)pyrimidine (5.63 g,48% yield). The product was carried on to the next step without furtherpurification. MS (ES+): m/z=223.2/224.3 (100/50) [MH⁺]. HPLC: t_(R)=0.84minute over 3 minutes. Purity: 77% [HPLC (LC/MS) at 220 nm].

Preparation of intermediate(3Z)-1-Cyclopropyl-4-(dimethylamino)-3-[2-(methylsulfanyl)pyrimidin-4-yl]but-3-en-2-one(3)

A solution of1-cyclopropyl-3-[2-(methylsulfanyl)pyrimidin-4-yl]propan-2-one (2)(216.3 mg, 0.973 mmol) in DMF-DMA (1303 μl, 9.73 mmol) was stirred at80° C. for 2 hours. The reaction was partitioned between water andEtOAc. The organic layer was separated, and the aqueous layer wasback-extracted. The organic extracts were combined, washed with brine,dried over sodium sulfate, then concentrated in vacuo. The crude productwas purified by Biotage™ silica gel chromatography [25 g ISOLUTE column,100% DCM to 10% MeOH/DCM] to obtain the desired product as aorange-yellow solid (186.8 mg, 69.2% yield). MS (ES+): m/z=278.2/279.2(100/50) [MH⁺]. HPLC: t_(R)=0.99 minute over 3 minutes. Purity: 100%[HPLC (LC/MS) at 220 nm].

Preparation of intermediate4′-(Cyclopropylmethyl)-2-(methylsulfanyl)-4,5′-bipyrimidine (4a)

A solution of(3Z)-1-cyclopropyl-4-(dimethylamino)-3-[2-(methylsulfanyl)pyrimidin-4-yl]but-3-en-2-one(3) (200 mg, 0.721 mmol), formamidine acetate (75 mg, 0.721 mmol), andK₂CO₃ (299 mg, 2.163 mmol) in DMF (6 mL) was stirred at 120° C. for 30minutes, followed by stirring at rt for 18 hours. The reaction waspartitioned between water and EtOAc. The organic layer was separated,and the aqueous layer was back-extracted. The organic extracts werecombined, washed with brine, dried over sodium sulfate, thenconcentrated in vacuo. The crude product was purified by Biotage™ silicagel chromatography [10 g SNAP column, 30% EtOAc/heptane to 100% EtOAc]to obtain the desired product as a white solid (62.5 mg, 29.4% yield).The desired product contained a small amount of an unknown by-productand was carried on to the next step without further purification. MS(ES+): m/z=259.3 (100) [MH⁺²]. HPLC: t_(R)=1.77 minutes over 3 minutes.Purity: 87.5% [HPLC (LC/MS) at 220 nm].

Preparation of intermediate4′-(cyclopropylmethyl)-2-(methylsulfinyl)-4,5′-bipyrimidine (5a)

To a solution of4′-(cyclopropylmethyl)-2-(methylsulfanyl)-4,5′-bipyrimidine (4a) (62.5mg, 0.242 mmol) in DCM (968 μl), mCPBA (65.1 mg, 0.290 mmol) was addedand the reaction mixture was stirred at rt for 1 hour. The crudereaction mixture was partitioned between saturated sodium bicarbonatesolution and DCM. The aqueous layer was separated and back-extractedtwice with DCM. The combined organic extracts were washed with brine,dried over sodium sulfate, then concentrated in vacuo. The crude productwas carried on to the next step without further purification. MS (ES+):m/z=275.2 (100) [MH⁺]. HPLC: t_(R)=0.72 minute over 3 minutes. Purity:100% [HPLC (LC/MS) at 220 nm].

Preparation ofTrans-4-{[4′-(cyclopropylmethyl)-4,5′-bipyrimidin-2-yl]amino}cyclohexanol(6a)

To a solution of4′-(cyclopropylmethyl)-2-(methylsulfinyl)-4,5′-bipyrimidine (46.0 mg,0.168 mmol) in DMSO (1 mL), 4-trans-aminocyclohexanol (97 mg, 0.838mmol) was added and the reaction was microwaved for 20 minutes at 160°C. Additional 4-trans-aminocyclohexanol (97 mg, 0.838 mmol) was added tothe reaction mixture, and the reaction was microwaved at 160° C. for anadditional 30 minutes. Almost no reaction (<10%) was observed by LC/MS.Additional 4-trans-aminocyclohexanol (194 mg, 1.676 mmol) was added, andthe reaction mixture was microwaved at 160° C. for additional 1 hour.The reaction was cooled to rt and the crude reaction mixture waspurified by reverse-phase HPLC [30-100% organic phase over 15 minutes]followed by Biotage™ silica gel chromatography [10 g SNAP column, 100%DCM to 10% MeOH/DCM] to obtain the desired product. The desired productwas further purified by a trituration with acetone to remove a yellowimpurity, and was dried over high vacuum for 5 hours to afford the titlecompound as a white solid (23.49 mg, 43.1% yield). 1H NMR (400 MHz,DMSO-d₆) δ ppm 0.14 (br. s., 2H) 0.41 (d, J=7.07 Hz, 2H) 1.07-1.37 (m,5H) 1.86 (t, J=14.40 Hz, 6H) 2.74-3.01 (m, 2H) 3.34-3.47 (m, 1H)3.59-3.77 (m, 1H) 4.50 (d, J=4.55 Hz, 1H) 6.81 (d, J=4.55 Hz, 1H) 7.21(d, J=7.58 Hz, 1H) 8.39 (d, J=5.05 Hz, 1H) 8.77 (br. s., 1H) 9.16 (s,1H). HRMS (ES+) for C18H23N5O.H⁺ [MH⁺]: calcd, 326.1981; found,326.1980. UV-LC: 100/100% UV purity at 254/214 nm; t_(R)=3.79 minutesover 7.75 minutes.

The compounds listed in Table 1 below were prepared using proceduresanalogous to those described above for the synthesis of Compound 6ausing the appropriate starting materials.

TABLE 1 Example R HRMS (ES+ m/z) HPLC t_(R) (min) 1H NMR 6b NH₂ M + 1 =341.2085 2.84 (400 MHz, DMSO-d₆) δ ppm 0.09 (br. s., 2 H) 0.37 (d, J =27.58 Hz, 2 H) 1.01-1.13 (m, 1 H) 1.14-1.39 (m, 4 H) 1.74-1.95 (m, 4 H)2.79 (br. s., 2 H) 3.35-3.45 (m, 1 H) 3.67 (dd, J = 7.83, 3.79 Hz, 1 H)4.51 (d, J = 4.04 Hz, 1 H) 6.69 (d, J = 5.05 Hz, 1 H) 6.85 (s, 2 H) 6.95(d, J = 28.08 Hz, 1 H) 8.24 (d, J = 5.05 Hz, 1 H) 8.31 (s, 1 H) 6cMethyl M + 1 = 340.2148 3.91 (400 MHz, DMSO-d₆) δ ppm 0.11 (br. s., 2 H)0.38 (d, J = 7.07 Hz, 2 H) 1.06-1.36 (m, 5 H) 1.85 (t, J = 14.15 Hz, 4H) 2.65 (s, 3 H) 2.73-2.95 (m, 2 H) 3.33-3.45 (m, 1 H) 3.59-3.78 (m, 1H) 4.50 (d, J = 4.55 Hz, 1 H) 6.78 (d, J = 5.05 Hz, 1 H) 7.16 (d, J =7.58 Hz, 1 H) 8.36 (d, J = 4.55 Hz, 1 H) 8.65 (s, 1 H) 6d Ethyl M + 1 =354.2290 4.46 (400 MHz, DMSO-d₆) δ ppm 0.13 (br. s., 2 H) 0.39 (d, J =7.58 Hz, 2 H) 1.06-1.36 (m, 8 H) 1.73-1.96 (m, 4 H) 2.07 (s, 2 H) 2.75-3.00 (m, 4 H) 3.37-3.50 (m, 5 H) 3.68 (dd, J = 7.33, 3.79 Hz, 1 H) 6.79(d, J = 5.05 Hz, 1 H) 7.16 (d, J = 8.08 Hz, 1 H) 8.36 (d, J = 5.05 Hz, 1H) 8.69 (br. s., 1 H) 6e

M + 1 = 355.2237 3.28 (400 MHz, DMSO-d₆) δ ppm 0.05-0.24 (m, 2 H) 0.38(d, J = 6.57 Hz, 2 H) 0.95- 1.15 (m, 1 H) 1.15-1.40 (m, 4 H) 1.74- 1.97(m, 4 H) 2.82 (br. s., 2 H) 2.85 (d, J = 5.05 Hz, 3 H) 3.34-3.46 (m, 1H) 3.58- 3.78 (m, 1 H) 4.51 (d, J = 4.55 Hz, 1 H) 6.69 (d, J = 5.05 Hz,1 H) 6.94 (d, J = 7.58 Hz, 1 H) 7.30 (br. s., 1 H) 8.24 (d, J = 4.55 Hz,1 H) 8.37 (br. s., 1 H) 6f

M + 1 = 356.2082 4.29 (400 MHz, DMSO-d₆) δ ppm 0.15 (br. s., 2 H) 0.42(d, J = 7.07 Hz, 2 H) 1.06-1.36 (m, 5 H) 1.85 (t, J = 14.15 Hz, 4 H)2.86 (br. s., 2 H) 3.33-3.48 (m, 1 H) 3.58-3.76 (m, 1 H) 3.97 (s, 3 H)4.51 (d, J = 4.04 Hz, 1 H) 6.77 (d, J = 5.05 Hz, 1 H) 7.12 (d, J = 8.08Hz, 1 H) 8.34 (d, J = 5.05 Hz, 1 H) 8.62 (br. s., 1 H)

Preparation of intermediate4′-(Cyclopropylmethyl)-N-methyl-2-(methylsulfanyl)-4,5′-bipyrimidin-2′-amine(4-1)

A solution of(3Z)-1-cyclopropyl-4-(dimethylamino)-3-[2-(methylsulfanyl)pyrimidin-4-yl]but-3-en-2-one(3) (810 mg, 2.92 mmol), N-methylguanidine (480 mg, 4.38 mmol), andK₂CO₃ (1211 mg, 8.76 mmol) in DMF (28 mL) was stirred at 120° C. for 2hours, followed by stirring at rt for 18 hours. The reaction waspartitioned between water and EtOAc. The organic layer was separated,and the aqueous layer was back-extracted. The organic extracts werecombined, washed with brine, dried over sodium sulfate, thenconcentrated in vacuo. The crude product was purified by Biotage™ silicagel chromatography [100 g SNAP column, 30% EtOAc/heptane to 100% EtOAc]to afford the desired product as a white solid (720 g, 86% yield). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 0.12 (br. s., 2H) 0.37 (d, J=7.07 Hz, 2H)1.07 (br. s., 1H) 2.81 (d, J=6.57 Hz, 2H) 2.87 (d, J=5.05 Hz, 3H) 7.39(d, J=5.05 Hz, 1H) 7.49 (br. s., 1H) 8.49 (br. s., 1H) 8.60 (d, J=5.05Hz, 1H). MS (ES+): m/z=288.2/289.2/290.2 (100/20/10) [MH⁺]. HPLC:t_(R)=1.28 minutes over 3 minutes. Purity: 100% [HPLC (LC/MS) at 220nm].

Preparation of intermediate4′-(Cyclopropylmethyl)-N-methyl-2-(methylsulfinyl)-4,5′-bipyrimidin-2′-amine(5-1)

To a solution of4′-(cyclopropylmethyl)-N-methyl-2-(methylsulfanyl)-4,5′-bipyrimidin-2′-amine(4-1) (770 mg, 2.68 mmol), m-CPBA (925 mg, 5.36 mmol) was added and thereaction mixture was stirred at rt for 2 hours. The reaction waspartitioned between water and DCM. The organic layer was separated, andthe aqueous layer was back-extracted. The organic extracts werecombined, washed with brine, dried over sodium sulfate, thenconcentrated in vacuo. The crude product was purified by Biotage™ silicagel chromatography [50 g SNAP column, 100% DCM to 10% MeOH/DCM] toobtain a mixture of the desired product and the corresponding sulfone(645 mg, 79% yield). MS (ES+): m/z=304.2/305.2 (100/20) [MH⁺]. HPLC:t_(R)=0.85 minute over 3 minutes. Purity: 73.2% [HPLC (LC/MS) at 220nm].

Examples 14a-14s General Method: Synthesis of 14a-d, 141-m, 14p-qPreparation of4′-Cyclopropylmethyl-N²-(6-methoxy-pyridin-3-yl)-N^(2′)-methyl-[4,5]bipyrimidinyl-2,2′-diamine(14a)

To a solution of 6-methoxypyridin-3-amine (61.4 mg, 0.494 mmol) in THF(5 mL) cooled to −78° C., lithium bis(trimethylsilyl)amide (1M in THF,0.494 mL, 0.494 mmol) was added dropwise under nitrogen. After thereaction was stirred at −78° C. for 10 minutes, a solution of4′-(cyclopropylmethyl)-N-methyl-2-(methylsulfinyl)-4,5′-bipyrimidin-2′-amine(5-1) (30 mg, 0.099 mmol) in THF (1 mL) was added to the reaction at−78° C. The reaction was slowly warmed up to rt, then the reaction wasallowed to stir for 1 hour. The reaction was quenched with saturatedammonium chloride solution, then concentrated in vacuo. The reaction wastaken up in acetonitrile, purified by reverse-phase HPLC [10-90% organicphase over 15 minutes], then further purified by Biotage™ silica gelchromatography [10 g SNAP column, 100% DCM to 7% MeOH/DCM] to afford thetitle compound as a white solid (19.49 mg, 46.0% yield). 1H NMR (400MHz, DMSO-d₆) δ ppm 0.04 (br. s., 2H) 0.34 (d, J=7.58 Hz, 2H) 1.01 (br.s., 1H) 2.77 (d, J=6.57 Hz, 2H) 2.86 (d, J=4.55 Hz, 3H) 3.74-3.86 (m,3H) 6.78 (d, J=9.09 Hz, 1H) 6.97 (d, J=5.05 Hz, 1H) 7.36 (d, J=4.04 Hz,1H) 7.99 (dd, J=8.59, 2.53 Hz, 1H) 8.35-8.50 (m, 3H) 9.46 (s, 1H). HRMS(ES+) for C19H21N7O.H⁺ [MH⁺]: calcd, 364.1886; found, 364.1891. UV-LC:94.60/100% UV purity at 254/214 nm; t_(R)=5.08 minutes over 7.75minutes.

General Method for Synthesis of 14e-k, 14n-o, 14r-s Preparation ofN²-Cyclohexyl-4′-cyclopropylmethyl-N^(2′)-methyl-[4,5′]bipyrimidinyl-2,2′-diamine(14e)

To a solution of4′-(cyclopropylmethyl)-N-methyl-2-(methylsulfinyl)-4,5′-bipyrimidin-2′-amine(5-1) (50 mg, 0.165 mmol) in DMSO (1 mL), cyclohexylamine (94 μL, 0.824mmol) was added, and the reaction was heated in the microwave at 160° C.for 10 minutes. The crude reaction was purified by reverse-phase HPLC[30-100% organic phase with 3% n-propanol modifier over 15 minutes]followed by Biotage™ silica gel chromatography [10 g SNAP column, 100%DCM to 10% MeOH/DCM] to obtain the pure desired product as a white solid(39.0 mg, 69.9% yield). 1H NMR (400 MHz, DMSO-d₆) δ ppm 0.04-0.20 (m,2H) 0.37 (d, J=7.58 Hz, 2H) 0.99-1.19 (m, 2H) 1.19-1.36 (m, 4H) 1.59 (d,J=11.62 Hz, 1H) 1.65-1.80 (m, 2H) 1.88 (d, J=8.59 Hz, 2H) 2.72-2.90 (m,5H) 3.63-3.80 (m, 1H) 6.68 (d, J=5.05 Hz, 1H) 6.96 (d, J=8.08 Hz, 1H)7.29 (br. s., 1H) 8.24 (d, J=5.05 Hz, 1H) 8.36 (br. s., 1H). HRMS (ES+)for C19H26N6.H⁺ [MH⁺]: calcd, 339.2297; found, 339.2312. UV-LC: 100% UVpurity at 254/214 nm; t_(R)=6.70 minutes over 7.75 minutes.

The compounds listed in Table 2 below were prepared using the proceduresas indicated above using the appropriate starting materials.

TABLE 2

HPLC t_(R) Example R MS (ES+ m/z) (min) 1H NMR 14a

M +1 = 364.1891 5.08 (400 MHz, DMSO-d₆) δ ppm 0.04 (br. s., 2 H) 0.34(d, J = 7.58 Hz, 2 H) 1.01 (br. s., 1 H) 2.77 (d, J = 6.57 Hz, 2 H) 2.86(d, J = 4.55 Hz, 3 H) 3.74-3.86 (m, 3 H) 6.78 (d, J = 9.09 Hz, 1 H) 6.97(d, J = 5.05 Hz, 1 H) 7.36 (d, J = 4.04 Hz, 1 H) 7.99 (dd, J = 8.59,2.53 Hz, 1 H) 8.35-8.50 (m, 3 H) 9.46 (s, 1 H) 14b

M + 1 = 333.1823 5.89 (400 MHz, DMSO-d₆) δ ppm 0.04 (br. s., 2 H) 0.34(d, J = 7.58 Hz, 2 H) 1.01 (br. m, 1 H) 2.81 (d, J = 7.07 Hz, 2 H) 2.87(d, J = 4.55 Hz, 3 H) 6.86-7.04 (m, 2 H) 7.27 (t, J = 8.08 Hz, 2 H) 7.36(d, J = 4.04 Hz, 1 H) 7.75 (d, J = 7.58 Hz, 2 H) 8.42 (br. s., 1 H) 8.48(d, J = 5.05 Hz, 1 H) 9.56 (s, 1 H). 14c

M + 1 = 334.1769 2.80 (400 MHz, DMSO-d₆) δ ppm 0.04 (br. m, 2 H) 0.35(d, J = 7.07 Hz, 2 H) 1.01 (br. s., 1 H) 2.83 (d, J = 7.07 Hz, 2 H) 2.87(d, J = 4.55 Hz, 3 H) 7.15 (d, J = 5.56 Hz, 1 H) 7.41 (d, J = 3.03 Hz, 1H) 7.77 (d, J = 6.57 Hz, 2 H) 8.35 (d, J = 6.57 Hz, 2 H) 8.45 (br. s., 1H) 8.59 (d, J = 5.05 Hz, 1 H) 10.07 (s, 1 H) 14d

M + 1 = 384.1943 4.99 (400 MHz, DMSO-d₆) δ ppm 0.03 (br. s., 3 H) 0.32(d, J = 7.07 Hz, 2 H) 1.03 (br. s., 1 H) 2.75-2.96 (m, 5 H) 7.12 (d, J =5.56 Hz, 1 H) 7.41 (d, J = 4.55 Hz, 1 H) 7.48- 7.67 (m, 2 H) 7.83 (d, J= 7.58 Hz, 1 H) 7.93 (d, J = 8.08 Hz, 1 H) 8.48 (br. s., 1 H) 8.59 (d, J= 5.05 Hz, 1 H) 8.79 (d, J = 2.02 Hz, 1 H) 9.10 (d, J = 2.53 Hz, 1 H)10.08 (s, 1 H) 14e

M + 1 = 339.2312 6.70 (400 MHz, DMSO-d₆) δ ppm 0.04- 0.20 (m, 2 H) 0.37(d, J = 7.58 Hz, 2 H) 0.99-1.19 (m, 2 H) 1.19- 1.36 (m, 4 H) 1.59 (d, J= 11.62 Hz, 1 H) 1.65-1.80 (m, 2 H) 1.88 (d, J = 8.59 Hz, 2 H) 2.72-2.90(m, 5 H) 3.63-3.80 (m, 1 H) 6.68 (d, J = 5.05 Hz, 1 H) 6.96 (d, J = 8.08Hz, 1 H) 7.29 (br. s., 1 H) 8.24 (d, J = 5.05 Hz, 1 H) 8.36 (br. s., 1H) 14f

M + 1 = 311.1976 5.86 (400 MHz, DMSO-d₆) δ ppm 0.10 (br. s., 2 H) 0.37(d, J = 7.58 Hz, 2 H) 0.97-1.20 (m, 1 H) 1.53-1.74 (m, 2 H) 1.89-2.06(m, 2 H) 2.16- 2.30 (m, 2 H) 2.72-2.93 (m, 5 H) 4.27-4.46 (m, 1 H) 6.71(d, J = 5.05 Hz, 1 H) 7.30 (d, J = 3.03 Hz, 1 H) 7.39 (d, J = 8.08 Hz, 1H) 8.25 (d, J = 5.05 Hz, 1 H) 8.36 (br. s., 1 H) 14g

M + 1 = 341.2090 4.85 (400 MHz, DMSO-d₆) δ ppm 0.04- 0.22 (m, 2 H) 0.37(d, J = 7.58 Hz, 2 H) 1.08 (br. s., 1 H) 1.44- 1.59 (m, J = 11.87,11.87, 11.62, 4.04 Hz, 2 H) 1.82 (dd, J = 12.38, 2.27 Hz, 2 H) 2.73-2.91(m, 5 H) 3.31-3.44 (m, 3 H) 3.87 (d, J = 11.12 Hz, 2 H) 3.91-4.03 (m, 1H) 6.72 (d, J = 5.05 Hz, 1 H) 7.11 (d, J = 8.08 Hz, 1 H) 7.30 (br. s., 1H) 8.27 (d, J = 5.05 Hz, 1 H) 8.37 (br. s., 1 H) 14h

M + 1 = 325.2 6.26 (400 MHz, DMSO-d₆) δ ppm 0.03- 0.23 (m, 2 H)0.29-0.46 (m, 2 H) 1.07 (br. s., 1 H) 1.41-1.60 (m, 4 H) 1.60-1.79 (m, 2H) 1.79- 2.00 (m, 2 H) 2.71-2.93 (m, 5 H) 4.09-4.26 (m, 1 H) 6.69 (d, J= 5.05 Hz, 1 H) 7.09 (d, J = 7.58 Hz, 1 H) 7.29 (d, J = 4.04 Hz, 1 H)8.25 (d, J = 5.05 Hz, 1 H) 8.36 (br. s., 1 H) 14i

M + 1 = 454.2926 5.17 (400 MHz, DMSO-d₆) δ ppm 0.08- 0.26 (m, 2 H) 0.38(d, J = 5.56 Hz, 2 H) 1.07 (br. s., 1 H) 1.15- 1.34 (m, 4 H) 1.34-1.45(m, 10 H) 1.89 (br. s., 4 H) 2.71-2.94 (m, 5 H) 3.17 (d, J = 5.05 Hz, 1H) 3.66 (dd, J = 11.37, 3.28 Hz, 1 H) 5.75 (s, 1 H) 6.62-6.80 (m, 2 H)6.95 (d, J = 8.08 Hz, 1 H) 7.29 (d, J = 4.04 Hz, 1 H) 8.24 (d, J = 5.05Hz, 1 H) 8.36 (br. s., 1 H) 14j

M + 1 = 354.2414 4.99 (400 MHz, DMSO-d₆) δ ppm 0.03- 0.22 (m, 2 H)0.32-0.51 (m, 2 H) 1.09 (br. s., 1 H) 1.38-1.66 (m, 4 H) 1.98-2.27 (m, 4H) 2.77- 2.92 (m, 2 H) 2.98 (s, 3 H) 3.05- 3.21 (m, J = 11.56, 11.56,3.92, 3.79 Hz, 1 H) 3.77-3.95 (m, 1 H) 6.74 (d, J = 5.05 Hz, 1 H) 8.26(d, J = 5.56 Hz, 1 H) 8.34 (s, 1 H) 14k

M + 1 = 355.2243 3.56 (400 MHz, DMSO-d₆) δ ppm 0.10 (br. s., 2 H) 0.36(d, J = 7.07 Hz, 2 H) 1.07 (br. s., 1 H) 1.46 (t, J = 12.13 Hz, 2 H)1.53-1.81 (m, 6 H) 2.08 (s, 1 H) 2.81 (d, J = 6.57 Hz, 2 H) 2.85 (d, J =5.05 Hz, 3 H) 3.74 (br. s., 2 H) 4.31 (d, J = 3.03 Hz, 1 H) 6.69 (d, J =5.05 Hz, 1 H) 6.95 (d, J = 7.58 Hz, 1 H) 7.29 (d, J = 3.03 Hz, 1 H) 8.24(d, J = 5.05 Hz, 1 H) 8.36 (br. s., 1 H) 14l

M + 1 = 334.1785 3.08 (400 MHz, DMSO-d₆) δ ppm 0.34 (d, J = 7.58 Hz, 2H) 1.01 (br. s., 1 H) 2.80 (d, J = 6.57 Hz, 2 H) 2.87 (d, J = 4.55 Hz, 3H) 7.05 (d, J = 5.05 Hz, 1 H) 7.31 (dd, J = 8.08, 4.55 Hz, 1 H) 7.39 (d,J = 4.04 Hz, 1 H) 8.11-8.25 (m, 2 H) 8.43 (br. s., 1 H) 8.51 (d, J =5.05 Hz, 1 H) 8.89 (d, J = 2.53 Hz, 1 H) 9.77 (s, 1 H) 14m

M + 1 = 363.1926 5.52 (400 MHz, DMSO-d₆) δ ppm 0.01- 0.12 (m, 2 H) 0.34(d, J = 7.58 Hz, 2 H) 1.00 (br. s., 1 H) 2.79 (d, J = 7.07 Hz, 2 H) 2.86(d, J = 4.55 Hz, 3 H) 3.72 (s, 3 H) 6.87 (m, 2 H) 6.91 (d, J = 5.05 Hz,1 H) 7.34 (d, J = 4.04 Hz, 1 H) 7.61 (m, 2 H) 8.30-8.48 (m, 2 H) 9.35(s, 1 H) 14n

M + 1 = 383.2184 3.71 (400 MHz, DMSO-d₆) δ ppm 0.11 (br. s., 2 H) 0.37(d, J = 7.58 Hz, 2 H) 1.08 (br. s., 1 H) 1.19-1.48 (m, 4 H) 1.94 (t, J =10.36 Hz, 4 H) 2.05-2.22 (m, 1 H) 2.70-2.96 (m, 5 H) 3.62-3.87 (m, 1 H)6.71 (d, J = 5.05 Hz, 1 H) 6.99 (d, J = 8.08 Hz, 1 H) 7.30 (br. s., 1 H)8.25 (d, J = 4.55 Hz, 1 H) 8.37 (br. s., 1 H) 14o

M + 1 = 369.2399 4.29 (400 MHz, MeOD) δ ppm 0.15 (d, J = 5.05 Hz, 2 H)0.30-0.49 (m, 2 H) 1.10 (br. s., 1 H) 1.22-1.48 (m, 5 H) 2.08 (ddd, J =8.72, 4.55, 4.42 Hz, 4 H) 2.85 (d, J = 6.57 Hz, 2 H) 2.98 (s, 3 H)3.13-3.28 (m, 1 H) 3.70-3.95 (m, 1 H) 6.70 (d, J = 5.05 Hz, 1 H) 8.23(d, J = 5.05 Hz, 1 H) 8.34 (s, 1 H) 14p*

M + 1 = 393.3 1.3 (400 MHz, MeOD) δ ppm 0.13 (d, J = 5.56 Hz, 2 H) 0.44(d, J = 7.07 Hz, 2 H) 1.01-1.16 (m, 1 H) 2.98 (d, J = 7.07 Hz, 2 H)3.03-3.10 (m, 4 H) 3.77 (s, 6 H) 6.24 (s, 1 H) 6.90 (d, J = 2.02 Hz, 2H) 7.04 (d, J = 5.56 Hz, 1 H) 8.45 (d, J = 5.05 Hz, 1 H) 8.52 (s, 1 H)14q*

M + 1 = 393.3 1.17 (400 MHz, MeOD) δ ppm 0.16 (d, J = 3.54 Hz, 2 H) 0.46(d, J = 7.07 Hz, 2 H) 1.11 (br. s., 1 H) 2.96 (d, 2 H) 3.09 (s, 3 H)3.87 (s, 6 H) 6.98 (d, J = 8.59 Hz, 1 H) 7.08 (d, J = 5.56 Hz, 1 H) 7.14(d, J = 8.08 Hz, 1 H) 7.31 (br. s., 1 H) 8.38 (d, J = 5.05 Hz, 1 H) 8.58(br. s., 1 H) 14r*

M + 1 = 354.2 0.65 (400 MHz, MeOD) δ ppm 0.20 (d, J = 4.55 Hz, 2 H)0.40-0.54 (m, 2 H) 1.12 (br. s., 1 H) 1.87 (d, J = 14.65 Hz, 2 H) 2.34(d, J = 14.15 Hz, 3 H) 2.87-3.00 (m, 7 H) 3.10- 3.21 (m, 2 H) 3.61 (d, 2H) 4.14- 4.29 (m, 1 H) 7.01 (d, J = 4.04 Hz, 1 H) 8.32 (d, J = 6.06 Hz,1 H) 8.55 (br. s., 1 H) (m, 1 H) 14s*

M + 1 = 314.2 (400 MHz, MeOD) δ ppm 0.37 (d, J = 5.05 Hz, 2 H) 0.55-0.71(m, 3 H) 1.32 (br. s., 1 H) 2.09-2.23 (m, 3 H) 3.13 (d, J = 6.57 Hz, 2H) 3.19 (d, J = 8.08 Hz, 2 H) 3.77 (t, J = 6.06 Hz, 2 H) 7.22 (d, J =2.53 Hz, 1 H) 8.46 (d, J = 6.06 Hz, 1 H) 8.75 (br. s., 1 H)

Preparation of intermediate4′-(Cyclopropylmethyl)-2-(methylthio)-4,5′-bipyrimidin-2′-amine (4-2)

To a solution of(Z)-1-cyclopropyl-4-(dimethylamino)-3-(2-(methylthio)pyrimidin-4-yl)but-3-en-2-one(3) (2.07 g, 7.46 mmol) in DMF (62.2 ml) was added potassium carbonate(3.09 g, 22.39 mmol) and guanidine hydrochloride (1.065 g, 11.19 mmol).The resulting suspension was stirred at 120° C. After 45 minutes, thereaction was complete. The reaction mixture was concentrated in vacuo,then was taken up in EtOAc. The organic solution was washed with water,followed by brine, dried over sodium sulfate, then concentrated invacuo. The crude residue was dried over high vacuum for 18 h to obtainthe desired product as a bright orange product (2.17 g, quant. yield).MS (ES+): m/z=250.1 (50) [MH⁺]. HPLC: t_(R)=1.13 min over 3 min. Purity:100% [HPLC (LC/MS) at 220 nm]. ¹H NMR (400 MHz, DMSO-d₆) d ppm 0.06-0.13(m, 2H) 0.33-0.41 (m, 2H) 0.96-1.11 (m, 1H) 2.52-2.57 (m, 3H) 2.79 (d,J=7.07 Hz, 2H) 7.03 (s, 2H) 7.39 (d, J=5.56 Hz, 1H) 8.44 (s, 1H) 8.60(d, J=5.56 Hz, 1H).

Preparation of intermediate4′-(cyclopropylmethyl)-2-(methylsulfinyl)-4,5′-bipyrimidin-2′-amine(5-2)

To a solution of4′-(cyclopropylmethyl)-2-(methylthio)-4,5′-bipyrimidin-2′-amine (4a)(2.17 g, 7.14 mmol) in DCM (14.29 ml) was added m-CPBA (1.761 g, 7.14mmol). Immediately after the addition of m-CPBA, the reaction completionwas observed. The reaction mixture was diluted with DCM and water. Theorganic layer was washed with saturated sodium bicarbonate and brine,dried with sodium sulfate, and concentrated in vacuo. The crude residuewas purified by Biotage flash chromatography [100 g SNAP column, elutedwith 1-15% MeOH/DCM] to obtain the desired product as a slightly paleyellow solid (1.47 g, 71% yield). MS (ES+): m/z=290.4/291.5 (100/10)[MH⁺]. HPLC: t_(R)=0.76 min over 3 min. Purity: 100% [HPLC (LC/MS) at220 nm].

Examples 15a-15y General Method for Synthesis of 15e-f, 15h-o, 15u-yPreparation of4′-Cyclopropylmethyl-N²-(3-methyl-isoxazol-5-yl)-[4,5]bipyrimidinyl-2,2′-diamine(15h)

To a solution of 3-methyl-isoxazol-5-ylamine in THF was added LiHMDS at−78° C., then the solution was stirred for 15 minutes, and4′-(cyclopropylmethyl)-2-(methylsulfinyl)-4,5′-bipyrimidin-2′-amine(5-2) in THF was added to the reaction mixture. The reaction was warmedto rt and stirred for 1 hour. The reaction mixture was quenched withsaturated ammonium chloride, extracted with ethyl acetate, dried overanhydrous sodium sulfate, and evaporated to give a crude product whichwas further purified by reverse-phase HPLC to give the desired product.

General Method for Synthesis of 15a-d, 15g, 15p-t, 16g Preparation of4′-(cyclopropylmethyl)-N2-(tetrahydro-2H-pyran-3-yl)-4,5′-bipyrimidine-2,2′-diamine(15d)

To a solution of4′-(cyclopropylmethyl)-2-(methylsulfinyl)-4,5′-bipyrimidin-2′-amine(5-2) (50 mg, 0.173 mmol) in DMSO (1 ml), was addedTetrahydro-pyran-3-ylamine HCl (119 mg, 0.864 mmol) and triethylamine(0.120 ml, 0.864 mmol) and the reaction was microwaved for 45 min at160° C. The reaction was purified directly by reverse phase HPLC with agradient of 10-90% acetonitrile in water over 15 minutes and thenfurther purified by flash chromatography with a gradient of 25-100%ethyl acetate in heptane to give the desired product as a white solid(7.36 mg).

The compounds listed in Table 3 below were prepared using the proceduresas indicated above using the appropriate starting materials.

TABLE 3 15

HPLC t_(R) Example R HRMS (ES+ m/z) (min) 1H NMR 15a

M + 1 = 382.2355 3.07 (400 MHz, DMSO-d₆) δ ppm 0.07-0.17 (m, 2 H) 0.37(d, J = 7.58 Hz, 2 H) 1.13-1.42 (m, 4 H) 1.77 (s, 3 H) 1.78-2.00 (m, 4H) 2.71-2.89 (m, 2 H) 3.41-3.55 (m, 1 H) 3.70 (d, J = 8.08 Hz, 1 H) 6.70(d, J = 5.05 Hz, 1 H) 6.85 (br. s., 2 H) 6.98 (d, J = 7.07 Hz, 1 H) 7.71(d, J = 7.58 Hz, 1 H) 8.25 (d, J = 5.05 Hz, 1 H) 8.32 (br. s., 1 H) 15b

M + 1 = 418.2040 3.29 (400 MHz, DMSO-d₆) δ ppm 0.04-0.20 (m, 2 H) 0.37(d, J = 7.07 Hz, 2 H) 1.06 (br. s., 1 H) 1.20-1.46 (m, 4 H) 1.92 (d, J =10.11 Hz, 4 H) 2.78 (d, J = 4.04 Hz, 2 H) 2.91 (s, 3 H) 3.08 (br. s., 1H) 3.67 (br. s., 1 H) 6.70 (d, J = 5.05 Hz, 1 H) 6.84 (s, 2 H) 6.93-7.08(m, 2 H) 8.25 (d, J = 5.05 Hz, 1 H) 8.31 (br. s., 1 H) 15c

M + 1 = 326.2107 2.96 (400 MHz, CDCl3) δ ppm 0.13- 0.18 (m, 2 H)0.41-0.46 (m, 2 H) 1.05-1.15 (m, 1 H) 1.36- 1.48 (m, 3 H) 1.97 (d, J =11.62 Hz, 3 H) 2.84 (d, J = 6.57 Hz, 2 H) 2.99- 3.14 (m, 3 H) 4.77 (d, J= 13.14 Hz, 2 H) 5.12 (s, 2 H) 6.58 (d, J = 5.05 Hz, 1 H) 8.34 (d, J =5.05 Hz, 1 H) 8.38 (s, 1 H) 15d

M + 1 = 327.1925 3.62 (400 MHz, CDCl3) δ ppm 0.14- 0.19 (m, 2 H)0.41-0.48 (m, 2 H) 1.06-1.15 (m, 1 H) 1.59- 1.75 (m, 2 H) 1.97-2.06 (m,1 H) 2.82 (d, J = 7.07 Hz, 2 H) 3.45-3.52 (m, 1 H) 3.61-3.68 (m, 1 H)3.69-3.76 (m, 1 H) 3.94 (dd, J = 11.12, 3.54 Hz, 3 H) 4.07-4.15 (m, 3 H)5.23 (s, 5 H) 5.45 (d, J = 6.57 Hz, 2 H) 6.64 (d, J = 5.05 Hz, 1 H) 8.30(d, J = 5.05 Hz, 1 H) 8.37 (s, 1 H) 15e

M + 1 = 320.1639 2.50 15f

M + 1 = 326.1192 3.98 15g

M + 1 = 329.2084 3.53 15h

M + 1 = 324.1583 4.28 (400 MHz, DMSO-d₆) δ ppm 0.00-0.04 (m, 2 H)0.31-0.37 (m, 2 H) 0.93-1.04 (m, 1 H) 2.17 (s, 3 H) 2.80 (d, J = 6.57Hz, 2 H) 6.18 (s, 1 H) 6.98 (s, 2 H) 7.19 (d, J = 5.05 Hz, 1 H) 8.39 (s,1 H) 8.58 (d, J = 5.05 Hz, 1 H) 11.16 (s, 1 H) 15i

M + 1 = 327.1131 3.63 15j

M + 1 = 337.1570 5.21 (400 MHz, DMSO-d₆) δ ppm 0.00-0.03 (m, 2 H)0.30-0.35 (m, 2 H) 0.93-1.02 (m, 1 H) 2.77 (d, J = 6.57 Hz, 2 H) 6.91(s, 2 H) 6.99 (d, J = 5.56 Hz, 1 H) 7.09-7.15 (m, 2 H) 7.72- 7.77 (m, 2H) 8.36 (s, 1 H) 8.46 (d, J = 5.05 Hz, 2 H) 9.61 (s, 1 H) 15k

M + 1 = 323.1625 4.21 15l

M + 1 = 358.1773 4.21 15m

M + 1 = 363.1574 4.81 15n

M + 1 = 376.1900 3.80 (400 MHz, DMSO-d₆) δ ppm 0.01-0.07 (m, 2 H)0.31-0.37 (m, 2 H) 0.94-1.02 (m, 1 H) 2.01 (s, 3 H) 2.82 (d, J = 6.57Hz, 2 H) 6.98 (d, J = 5.05 Hz, 1 H) 7.47 (d, J = 9.09 Hz, 1 H) 7.62 (d,J = 9.09 Hz, 1 H) 8.40 (br. s., 1 H) 8.47 (d, J = 5.05 Hz, 1 H) 9.55 (s,1 H) 9.83 (s, 1 H) 15o

M + 1 = 353.1280 5.83 15p

M + 1 = 386.2098 4.44 15q

M + 1 = 334.1785 3.90 15r

M + 1 = 334.1794 3.80 15s

M + 1 = 356.2215 3.48 15t

M + 1 = 337.1896 3.53 15u

M + 1 = 334.1782 2.50 (400 MHz, DMSO-d₆) δ ppm 0.00-0.04 (m, 2 H)0.30-0.35 (m, 2 H) 0.93-1.01 (m, 1 H) 2.76 (d, J = 6.57 Hz, 2 H) 4.77(br. s., 2 H) 6.50 (d, J = 8.59 Hz, 2 H) 6.83 (d, J = 5.05 Hz, 1 H) 6.90(s, 2 H) 7.28 (d, J = 8.59 Hz, 2 H) 8.32 (s, 1 H) 8.35 (d, J = 5.56 Hz,1 H) 9.05 (s, 1 H) 15v

M + 1 = 354.1244 4.95 15w

M + 1 = 372.1954 4.49 (400 MHz, DMSO-d₆) δ ppm 0.00-0.04 (m, 2 H)0.29-0.34 (m, 2 H) 0.94-1.02 (m, 1 H) 2.35 (s, 3 H) 2.78 (d, J = 6.57Hz, 2 H) 6.85-6.89 (m, 3 H) 7.15 (d, J = 8.59 Hz, 1 H) 7.21 (dd, J =8.59, 2.02 Hz, 1 H) 7.74 (s, 1 H) 8.34 (s, 1 H) 8.40 (d, J = 5.05 Hz, 1H) 9.21 (s, 1 H) 10.71 (s, 1 H) 15x

M + 1 = 344.1626 5.11 (400 MHz, DMSO-d₆) δ ppm 0.00-0.03 (m, 2 H)0.30-0.36 (m, 2 H) 0.92-1.02 (m, 1 H) 2.79 (d, J = 7.07 Hz, 2 H) 6.97(s, 2 H) 7.14 (d, J = 5.05 Hz, 1 H) 7.73 (d, J = 9.09 Hz, 2 H) 7.98 (d,J = 9.09 Hz, 2 H) 8.39 (s, 1 H) 8.57 (d, J = 5.56 Hz, 1 H) 10.18 (s, 1H) 15y

M + 1 = 362.2092 3.65

Preparation of intermediate1-(4′-(Cyclopropylmethyl)-2-(methylthio)-4,5′-bipyrimidin-2′-ylamino)-2-methylpropan-2-ol(4-3)

To a solution of(Z)-1-cyclopropyl-4-(dimethylamino)-3-(2-(methylthio)pyrimidin-4-yl)but-3-en-2-one(3) in DMF (4 mL), 1-(2-hydroxy-2-methylpropyl)guanidine (529 mg, 3.15mmol) and potassium carbonate (872 mg, 6.31 mmol) were added, and thereaction mixture was stirred at 120° C. for 2 h. The reaction mixturewas purified by a reverse-phase Gilson HPLC [30-90% organic phase over15 min] followed by a Biotage silica gel chromatography [10 g SNAPcolumn, 100% DCM to 12% MeOH/DCM] to obtain the desired product as aglassy solid (90 mg, 21% yield). MS (ES+): m/z=392.2/393.2/394.3(100/40/10) [MH⁺]. HPLC: t_(R)=1.12 min over 3 min. Purity: 100% [HPLC(LC/MS) at 220 nm].

Preparation of intermediate1-(4′-(cyclopropylmethyl)-2-(methylsulfinyl)-4,5′-bipyrimidin-2′-ylamino)-2-methylpropan-2-ol(5-3)

To a solution of1-(4′-(Cyclopropylmethyl)-2-(methylthio)-4,5′-bipyrimidin-2′-ylamino)-2-methylpropan-2-ol(90 mg, 0.261 mmol) in DCM (521 μl), mCPBA (70.6 mg, 0.287 mmol) wasadded in portions, and the reaction mixture was stirred at rt for 1 h.The crude product was purified by a Biotage silica gel chromatography[10 g SNAP column, 100% DCM to 12% MeOH/DCM] to obtain the desiredproduct as a yellow solid (38 mg, 40% yield). MS (ES+): m/z=362.2 (100)[MH⁺]. HPLC: t_(R)=0.90 min over 3 min. Purity: 100% [HPLC (LC/MS) at220 nm].

1-(2-(2-chloropyridin-4-ylamino)-4′-(cyclopropylmethyl)-4,5′-bipyrimidin-2′-ylamino)-2-methylpropan-2-ol(16a)

To a solution of 4-amino-2-chloropyridine (53.3 mg, 0.415 mmol) in THF(277 μl) cooled to −78° C. under nitrogen, LiHMDS (415 μl, 0.415 mmol)was added dropwise. The reaction mixture was warmed up to rt, then wasstirred for 30 min. To the reaction mixture cooled back to −78° C.,1-(4′-(cyclopropylmethyl)-2-(methylsulfinyl)-4,5′-bipyrimidin-2′-ylamino)-2-methylpropan-2-ol(5-3) (50 mg, 0.138 mmol) was added, and the reaction mixture was warmedup to rt, then was stirred for additional 1 h. According to LC/MS, thereaction was complete. The crude product was purified by reverse-phaseHPLC [30-100% organic phase over 15 min] followed by Biotage silica gelchromatography [10 g SNAP column, 100% DCM to 12% MeOH/DCM] to obtainthe desired product (29 mg, 49%).

4-(4′-(cyclopropylmethyl)-2′-(2-hydroxy-2-methylpropylamino)-4,5′-bipyrimidin-2-ylamino)benzonitrile(16b)

To a solution of 4-aminobenzonitrile (16.34 mg, 0.138 mmol) in THF (277μl) cooled to −78° C. under nitrogen, LiHMDS (415 μl, 0.415 mmol) wasadded dropwise. The reaction mixture was warmed up to rt, then wasstirred for 30 min. To the reaction mixture cooled back to −78° C.,1-(4′-(cyclopropylmethyl)-2-(methylsulfinyl)-4,5′-bipyrimidin-2′-ylamino)-2-methylpropan-2-ol(5-3) (50 mg, 0.138 mmol) was added, and the reaction mixture was warmedup to rt, then was stirred for additional 1 h. According to LC/MS, thereaction was complete. The crude product was purified by reverse-phaseHPLC [30-100% organic phase over 15 min] followed by Biotage silica gelchromatography [10 g SNAP column, 100% DCM to 12% MeOH/DCM] to obtainthe desired product (16 mg, 28%).

1-(4′-(cyclopropylmethyl)-2-(4-(methylsulfonyl)phenylamino)-4,5′-bipyrimidin-2′-ylamino)-2-methylpropan-2-ol(16d)

To a solution of 4-sulfonylaniline (71.1 mg, 0.415 mmol) in THF (277 μl)cooled to −78° C. under nitrogen, LiHMDS (69.4 mg, 0.415 mmol) was addeddropwise. The reaction mixture was warmed up to rt, then was stirred for30 min. To the reaction mixture cooled back to −78° C.,1-(4′-(cyclopropylmethyl)-2-(methylsulfinyl)-4,5′-bipyrimidin-2′-ylamino)-2-methylpropan-2-ol(5-3) (50 mg, 0.138 mmol) was added, and the reaction mixture was warmedup to rt, then was stirred for additional 1 h. According to LC/MS, thereaction was complete. The crude product was purified by reverse-phaseHPLC [30-100% organic phase over 15 min] followed by Biotage silica gelchromatography [10 g SNAP column, 100% DCM to 12% MeOH/DCM] to obtainthe desired product (11 mg, 17%).

TABLE 4 16

HPLC t_(R) Example R HRMS (ES+ m/z) (min) 1H NMR 16a

M + 1 = 426.1819 5.57 (400 MHz, DMSO-d₆) δ ppm 0.05 (br. s., 2 H) 0.37(d, J = 6.57 Hz, 2 H) 0.97 (br. s., 1 H) 1.08 (d, J = 7.07 Hz, 1 H) 1.13(s, 7 H) 2.83 (d, J = 7.07 Hz, 2 H) 3.39 (d, J = 3.54 Hz, 2 H) 4.57 (s,1 H) 7.17 (br. s., 1 H) 7.23 (d, J = 5.05 Hz, 2 H) 7.64-7.73 (m, 1 H)8.01 (s, 1 H) 8.17 (d, J = 5.56 Hz, 1 H) 8.45 (s, 1 H) 8.63 (d, J = 5.05Hz, 1 H) 10.35 (s, 1 H) 16b

M + 1 = 416.2200 5.71 (400 MHz, DMSO-d₆) δ ppm 0.04 (br. s., 2 H) 0.35(d, J = 7.07 Hz, 2 H) 0.99 (d, J = 14.15 Hz, 1 H) 1.13 (s, 6 H) 2.81 (d,J = 6.57 Hz, 2 H) 3.38 (d, J = 5.56 Hz, 2 H) 4.57 (br. s., 1 H) 7.15 (d,J = 5.05 Hz, 1 H) 7.22 (br. s., 1 H) 7.73 (m, J = 9.09 Hz, 2 H) 7.98 (m,J = 8.59 Hz, 2 H) 8.43 (s, 1 H) 8.58 (d, J = 5.05 Hz, 1 H) 10.17 (s, 1H) 16c

M + 1 = 409.2154 6.09 (400 MHz, DMSO-d₆) δ ppm 0.04 (br. s., 2 H) 0.35(d, J = 7.07 Hz, 2 H) 0.89-1.07 (m, 1 H) 1.12 (s, 6 H) 2.79 (d, J = 6.57Hz, 2 H) 3.37 (d, J = 5.56 Hz, 2 H) 4.57 (br. s., 1 H) 6.99 (d, J = 5.05Hz, 1 H) 7.12 (t, J = 8.84 Hz, 2 H) 7.14-7.22 (m, 1 H) 7.74 (dd, J =9.09, 5.05 Hz, 2 H) 8.40 (s, 1 H) 8.47 (d, J = 5.05 Hz, 1 H) 9.59 (s, 1H) 16d

M + 1 = 469.2026 5.01 (400 MHz, MeOD) δ ppm 0.09 (d, J = 4.55 Hz, 2 H)0.36-0.48 (m, 2 H) 1.08 (d, J = 13.14 Hz, 1 H) 1.21-1.30 (m, 6 H) 2.88(d, J = 6.57 Hz, 2 H) 3.05-3.13 (m, 3 H) 3.52 (s, 2 H) 7.06 (d, J = 5.56Hz, 1 H) 7.84 (m, J = 8.59 Hz, 2 H) 8.01 (m, J = 9.09 Hz, 2 H) 8.44 (s,1 H) 8.53 (d, J = 5.05 Hz, 1 H) 16e

M + 1 = 425.1857 6.47 (400 MHz, MeOD) δ ppm 0.02- 0.15 (m, 2 H)0.29-0.51 (m, 2 H) 0.96-1.16 (m, 1 H) 1.16- 1.34 (m, 6 H) 2.85 (d, J =7.07 Hz, 2 H) 3.51 (s, 2 H) 6.94 (d, J = 5.05 Hz, 1 H) 7.26 (m, J = 8.59Hz, 2 H) 7.68 (m, J = 9.09 Hz, 2 H) 8.40 (s, 1 H) 8.43 (d, J = 5.56 Hz,1 H) 16f

M + 1 = 448.2443 4.41 (400 MHz, DMSO-d₆) δ ppm 0.06 (d, J = 2.53 Hz, 2H) 0.36 (d, J = 7.58 Hz, 2 H) 1.13 (s, 6 H) 2.01 (s, 3 H) 2.82 (d, J =7.07 Hz, 2 H) 3.38 (br. s., 2 H) 6.97 (d, J = 5.05 Hz, 1 H) 7.27 (d, J =8.59 Hz, 1 H) 7.47 (d, J = 9.09 Hz, 2 H) 7.61 (d, J = 8.59 Hz, 2 H) 8.43(s, 1 H) 8.45 (d, J = 5.05 Hz, 1 H) 9.50 (s, 1 H) 9.80 (s, 1 H) 16g

M + 1 = 490.2603 3.82 (400 MHz, DMSO-d₆) δ ppm 0.13 (d, J = 10.61 Hz, 2H) 0.39 (d, J = 7.07 Hz, 2 H) 0.96-1.17 (m, 8 H) 1.19-1.47 (m, 4 H) 1.92(d, J = 10.11 Hz, 4 H) 2.80 (br. s., 2 H) 2.91 (s, 3 H) 3.08 (d, J =2.02 Hz, 1 H) 3.67 (br. s., 1 H) 4.58 (br. s., 1 H) 6.71 (d, J = 5.05Hz, 1 H) 6.93-7.19 (m, 3 H) 8.25 (d, J = 5.05 Hz, 1 H) 8.36 (br. s., 1H)

Example 7 Preparation of1-Cyclopropyl-3-[2-(methylsulfinyl)pyrimidin-4-yl]propan-2-one (7)

To a solution of1-cyclopropyl-3-[2-(methylsulfanyl)pyrimidin-4-yl]propan-2-one (2) (3.00g, 13.49 mmol) in DCM (54.0 mL) at rt, mCPBA (3.99 g, 16.19 mmol) wasadded in portions. The reaction mixture was stirred at rt for 1 hour.The reaction was partitioned between saturated sodium carbonate solutionand DCM and the aqueous layer was back-extracted. The organic extractswere combined, washed with brine, dried over sodium sulfate, thenconcentrated in vacuo. The crude product was purified by Biotage™ silicagel chromatography [100% DCM to 5% MeOH/DCM] to afford the desiredproduct as a viscous yellow oil (1.88 g, 58.5% yield), which was stillcontaminated with residual m-chlorobenzoic acid and carried on to thenext step. MS (ES+): m/z=239.2 (100) [MH⁺²]. HPLC: t_(R)=0.73 minuteover 3 minutes. Purity: 67.7% [HPLC (LC/MS) at 220 nm].

Example 8 Preparation of1-Cyclopropyl-3-[2-(pyridin-4-ylamino)pyrimidin-4-yl]propan-2-one (8)

To a solution of 4-aminopyridine (328 mg, 3.49 mmol) in THF (2.344 mL)cooled to −78° C. was added LHMDS (583 mg, 3.49 mmol). The reaction waswarmed to rt and stirred for 15 minutes. The reaction was again cooledto −78° C. and1-cyclopropyl-3-[2-(methylsulfinyl)pyrimidin-4-yl]propan-2-one (7) (277mg, 1.162 mmol) was added as a solution in THF (2 mL). The reaction waswarmed to rt and stirred for 1 hour. The reaction was quenched by slowaddition of saturated ammonium chloride and the volatiles evaporated.The residue was then partitioned between water and DCM. The organiclayer was washed with brine, dried with sodium sulfate, and concentratedin vacuo. The crude residue was purified by Biotage™ silica gelchromatography [2-10% MeOH in DCM with 1% triethylamine] to afford thedesired product as a yellow oil (269 mg, 86%). MS (ES+): m/z=269.2 (100)[MH⁺²]. HPLC: t_(R)=0.69 minute over 3 minutes. Purity: >95% [HPLC(LC/MS) at 220 nm].

Example 9 Preparation of(3Z)-1-Cyclopropyl-4-(dimethylamino)-3-[2-(pyridin-4-ylamino)pyrimidin-4-yl]but-3-en-2-one(9)

1-Cyclopropyl-3-[2-(pyridin-4-ylamino)pyrimidin-4-yl]propan-2-one (8)(269 mg, 1.003 mmol) was taken up in DMF-DMA (5.369 mL, 40.1 mmol) andstirred at 80° C. for 30 minutes. The solvent was evaporated and theresidue partitioned between DCM and water. The organic layer was washedwith saturated sodium bicarbonate and brine, dried with sodium sulfate,and concentrated in vacuo. The crude residue was purified by Biotage™silica gel chromatography [1-13% MeOH in DCM with 1% triethylamine] toafford the desired product as an orange/brown foam (320 mg, 99% yield).MS (ES+): m/z=324.3 (100) [MH⁺²]. HPLC: t_(R)=0.88 minute over 3minutes. Purity: >90% [HPLC (LC/MS) at 220 nm].

Examples 10a-10v General method for synthesis of4′-(cyclopropylmethyl)-N²-pyridin-4-yl-4,5′-bipyrimidine-2,2′-diamines10a-v Preparation of4′-Cyclopropylmethyl-N²-pyridin-4-yl-[4,5′]bipyrimidinyl-2,2′-diamine(10a)

To a solution of(3Z)-1-cyclopropyl-4-(dimethylamino)-3-[2-(pyridin-4-ylamino)pyrimidin-4-yl]but-3-en-2-one(9) (80 mg, 0.247 mmol) in DMF (2061 μl), Guanidine HCl (35.3 mg, 0.371mmol) and potassium carbonate (103 mg, 0.742 mmol) were added and thereaction was heated at 60° C. for 4 hours. The crude product waspurified by reverse-phase HPLC [30-90% organic phase over 15 minutes]followed by Biotage™ silica gel chromatography [10 g SNAP column, 100%DCM to 12% MeOH/DCM] to obtain the desired product as a white solid(24.72 mg, 31.3% yield). ¹H NMR (400 MHz, MeOD) δ ppm 0.01-0.14 (m, 2H)0.39 (q, J=6.06 Hz, 2H) 0.94-1.10 (m, 1H) 2.87 (d, J=7.07 Hz, 2H) 7.10(d, J=5.05 Hz, 1H) 7.83 (d, J=6.57 Hz, 2H) 8.30 (d, J=6.57 Hz, 2H) 8.41(s, 1H) 8.57 (d, J=5.05 Hz, 1H). HRMS (ES+) for C17H17N7.H⁺ [MH⁺]:calcd, 320.1624; found, 320.1636. UV-LC: 100% UV purity at 254/214 nm;t_(R)=4.67 minute over 7.75 minutes.

Preparation ofN2′-cyclopentyl-4′-(cyclopropylmethyl)-N2-(pyridin-4-yl)-4,5′-bipyrimidine-2,2′-diamine(10e)

To a solution oftert-butyl(tert-butoxycarbonylamino)(cyclopentylamino)methylenecarbamate(74.3 mg, 0.186 mmol) in DCM (515 μl), TFA (143 μl, 1.855 mmol) wasadded dropwise, and the reaction mixture was stirred at rt. After 2hours the Boc deprotection was only ˜50% complete and additional TFA(143 μl, 1.855 mmol) was added. The reaction mixture was stirred at rtfor an additional 2 hours, after which time the deprotection wascomplete by LC/MS to give the Boc-deprotected intermediate(MW=127.1906). The reaction mixture was concentrated in vacuo, rinsedtwice with diethyl ether, then taken up in DMF (515 μl). To the reactionmixture,(Z)-1-cyclopropyl-4-(dimethylamino)-3-(2-(pyridin-4-ylamino)pyrimidin-4-yl)but-3-en-2-one(9) (40 mg, 0.124 mmol) and potassium carbonate (68.4 mg, 0.495 mmol)were added, and the reaction mixture was stirred at 60° C. for 4 hfollowed by 40° C. for 18 hours. The crude product was purified byreverse-phase HPLC [30-90% organic phase over 15 minutes] followed byBiotage™ silica gel chromatography to obtain the desired product (16.1mg, 32%).

Preparation of(S)-1-[4′-Cyclopropylmethyl-2-(pyridin-4-ylamino)-[4,5′]bipyrimidinyl-2′-ylamino]-propan-2-ol(10k)

To a solution of(Z)-1-cyclopropyl-4-(dimethylamino)-3-(2-(pyridin-4-ylamino)pyrimidin-4-yl)but-3-en-2-one(9) (50 mg, 0.155 mmol) in DMF (1288 μl),(S)-1-(2-hydroxypropyl)guanidine (18.11 mg, 0.115 mmol), and potassiumcarbonate (64.1 mg, 0.464 mmol) were added, and the reaction mixture wasstirred at 90° C. for 3 hours. The crude product was purified byreverse-phase HPLC [30-90% organic phase over 15 minutes] followed byBiotage™ silica gel chromatography [10 g SNAP column, 100% DCM to 12%MeOH/DCM] to obtain the desired product (19.76 mg, 33%).

Preparation of2-(4′-(cyclopropylmethyl)-2-(pyridin-4-ylamino)-4,5′-bipyrimidin-2′-ylamino)ethanol(10m)

To a solution(3Z)-1-cyclopropyl-4-(dimethylamino)-3-[2-(pyridin-4-ylamino)pyrimidin-4-yl]but-3-en-2-one(9) (50 mg, 0.155 mmol) in DMF (1288 μl), 1-(2-hydroxyethyl)guanidine(23.92 mg, 0.232 mmol) and potassium carbonate (107 mg, 0.773 mmol) wereadded dropwise, and the reaction mixture was stirred at 120° C. for 2hours. The crude product was purified by reverse-phase HPLC [30-90%organic phase over 15 minutes] followed by Biotage™ silica gelchromatography [10 g SNAP column, 100% DCM to 12% MeOH/DCM] to obtainthe desired product (9.13 mg, 16.3%).

Preparation of(S)-2-(4′-(cyclopropylmethyl)-2-(pyridin-4-ylamino)-4,5′-bipyrimidin-2′-ylamino)propan-1-ol(10q)

To a solution of(Z)-1-cyclopropyl-4-(dimethylamino)-3-(2-(pyridin-4-ylamino)pyrimidin-4-yl)but-3-en-2-one(9) (50 mg, 0.155 mmol) in DMF (541 μl),(S)-1-(1-hydroxypropan-2-yl)guanidine (147 mg, 0.773 mmol) and potassiumcarbonate (214 mg, 1.546 mmol) were added, and the reaction mixture wasstirred at 90° C. for 3 hours. The crude product was purified byreverse-phase HPLC [30-90% organic phase over 15 minutes] followed byBiotage™ silica gel chromatography [10 g SNAP column, 100% DCM to 12%MeOH/DCM] to obtain the desired product (23.9 mg, 41%).

Preparation of4′-(cyclopropylmethyl)-N2′-neopentyl-N2-(pyridin-4-yl)-4,5′-bipyrimidine-2,2′-diamine(10r)

To a solution oftert-butyl(tert-butoxycarbonylamino)(neopentylamino)methylenecarbamate(122 mg, 0.371 mmol) in DCM (515 μl), TFA (476 μl, 6.18 mmol) was addeddropwise, and the reaction mixture was stirred at rt for 2 hours. Thereaction mixture was concentrated in vacuo, rinsed twice with diethylether, then taken up in DMF (515 μl). To the reaction mixture,(Z)-1-cyclopropyl-4-(dimethylamino)-3-(2-(pyridin-4-ylamino)pyrimidin-4-yl)but-3-en-2-one(9) (40 mg, 0.124 mmol) and K₂CO₃ (85 mg, 0.618 mmol) were added and thereaction mixture was stirred at 120° C. for 2 hours. The crude productswere purified by reverse-phase HPLC [30-90% organic phase over 15minutes] followed by Biotage™ silica gel chromatography [10 g SNAPcolumn, 100% DCM to 12% MeOH/DCM] to obtain the desired product (18.37mg, 38%).

Preparation of1-(4′-(cyclopropylmethyl)-2-(pyridin-4-ylamino)-4,5′-bipyrimidin-2′-ylamino)-2-methylpropan-2-ol(10t)

To a solution of(Z)-1-cyclopropyl-4-(dimethylamino)-3-(2-(pyridin-4-ylamino)pyrimidin-4-yl)but-3-en-2-one(9) (50 mg, 0.155 mmol) in DMF (1288 μl),1-(2-hydroxy-2-methylpropyl)guanidine and potassium carbonate (107 mg,0.773 mmol) were added and the reaction mixture was stirred at 120° C.for 2 hours. The crude product was purified by reverse-phase HPLC[30-90% organic phase over 15 minutes] followed by Biotage™ silica gelchromatography [10 g SNAP column, 100% DCM to 12% MeOH/DCM] to obtainthe desired product (23.8 mg, 39%).

TABLE 5

Example R HRMS (ES+ m/z) HPLC t_(R) (min) 1H NMR 10a NH2 M + 1 =320.1636 4.67 (400 MHz, MeOD) δ ppm 0.01- 0.14 (m, 2 H) 0.39 (q, J =6.06 Hz, 2 H) 0.94-1.10 (m, 1 H) 2.87 (d, J = 7.07 Hz, 2 H) 7.10 (d, J =5.05 Hz, 1 H) 7.83 (d, J = 6.57 Hz, 2 H) 8.30 (d, J = 6.57 Hz, 2 H) 8.41(s, 1 H) 8.57 (d, J = 5.05 Hz, 1H) 10b

M + 1 = 348.1950 3.13 (400 MHz, MeOD) δ ppm 0.04 (br. s., 2 H) 0.36 (br.s., 2 H) 1.00 (br. s., 1 H) 1.16 (t, J = 7.03 Hz 3 H) 2.82 (d, J = 6.53Hz, 2 H) 3.37 (d, J = 6.53 Hz, 2 H) 7.16 (d, J = 5.02 Hz, 1 H) 7.55 (t,J = 5.27 Hz, 1 H) 7.77 (d, J = 6.53 Hz, 2 H) 8.35 (d, J = 6.53 Hz, 2 H)8.44 (s, 1 H) 8.59 (d, J = 5.52 Hz, 1 H) 10.10 (s, 1 H) 10c

M + 1 = 410.2099 3.74 (400 MHz, MeOD) δ ppm 0.05 (q, J = 5.05 Hz, 2 H)0.26-0.45 (m, 2 H) 0.97-1.11 (m, 1 H) 2.86 (d, J = 7.07 Hz, 2 H) 4.67(s, 2 H) 7.07 (d, J = 5.05 Hz, 1 H) 7.17-7.25 (m, 1 H) 7.29 (t, J = 7.58Hz, 2 H) 7.34-7.41 (m, 2 H) 7.82 (d, J = 6.57 Hz, 2 H) 8.29 (d, J = 6.57Hz, 2 H) 8.42 (s, 1 H) 8.53 (d, J = 5.05 Hz, 1 H) 10d

M + 1 = 376.2253 3.64 (400 MHz, MeOD) δ ppm 0.03- 0.26 (m, 2 H)0.27-0.55 (m, 2 H) 0.98 (d, J = 6.53 Hz, 6 H) 1.02-1.20 (m, 1 H)1.85-2.08 (m, 1 H) 2.88 (d, J = 7.03 Hz, 2 H) 3.28 (d, J = 6.02 Hz, 2 H)7.09 (d, J = 5.02 Hz, 1 H) 7.70-7.96 (m, 2 H) 8.19-8.35 (m, 2 H) 8.41(s, 1 H) 8.55 (d, J = 5.02 Hz, 1 H) 10e

M + 1 = 388.2248 3.74 (400 MHz, MeOD) δ ppm 0.09 (d, J = 4.02 Hz, 2 H)0.29-0.51 (m, 2 H) 1.07 (br. s., 1 H) 1.52-1.71 (m, 4 H) 1.72-1.84 (m, 2H) 2.05 (dt, J = 12.05, 6.02 Hz, 2 H) 2.87 (d, J = 6.53 Hz, 2 H)4.19-4.43 (m, 1 H) 7.09 (d, J = 5.52 Hz, 1 H) 7.84 (d, J = 6.53 Hz, 2 H)8.29 (d, J = 6.53 Hz, 2 H) 8.41 (s, 1 H) 8.55 (d, J = 5.02 Hz, 1 H) 10f

M + 1 = 374.2105 3.55 (400 MHz, MeOD) δ ppm 0.09 (d, J = 4.52 Hz, 2 H)0.31-0.48 (m, 2 H) 1.07 (br. s., 1 H) 1.61-1.89 (m, 2 H) 1.93-2.13 (m, 2H) 2.30-2.51 (m, 2 H) 2.87 (d, J = 6.53 Hz, 2 H) 4.37-4.62 (m, 1 H) 7.08(d, J = 5.02 Hz, 1 H) 7.83 (d, J = 7.03 Hz, 2 H) 8.29 (d, J = 6.52 Hz, 2H) 8.40 (s, 1 H) 8.54 (d, J = 5.52 Hz, 1 H) 10g

M + 1 = 404.2197 3.12 (400 MHz, MeOD) δ ppm 0.10 (d, J = 5.02 Hz, 2 H)0.41 (d, J = 7.53 Hz, 2 H) 0.95-1.19 (m, 1 H) 1.54-1.76 (m, 2 H)1.95-2.09 (m, 2 H) 2.88 (d, J = 7.03 Hz, 2 H) 3.51-3.63 (m, 2 H) 4.00(d, J = 11.04 Hz, 2 H) 4.05- 4.22 (m, 1 H) 7.10 (d, J = 5.52 Hz, 1 H)7.84 (d, J = 6.53 Hz, 2 H) 8.30 (d, J = 6.52 Hz, 2 H) 8.43 (s, 1 H)8.53- 8.60 (m, 1 H) 10h

M + 1 = 424.2264 3.93 (400 MHz, DMSO-d₆) δ ppm 0.30 (br. s., 8 H) 0.97(t, J = 7.07 Hz, 4 H) 1.48 (d, J = 7.07 Hz, 12 H) 2.80 (br. s., 7 H)5.10-5.28 (m, 4 H) 7.12 (d, J = 5.56 Hz, 4 H) 7.15-7.25 (m, 4 H) 7.30(t, J = 7.58 Hz, 8 H) 7.42 (d, J = 7.58 Hz, 8 H) 7.75 (d, J = 6.06 Hz, 8H) 8.06 (d, J = 8.08 Hz, 4 H) 8.34 (d, J = 6.06 Hz, 8 H) 8.41 (br. s., 4H) 8.57 (d, J = 5.05 Hz, 4 H) 10.04 (s, 4 H) 10i

M + 1 = 376.2248 3.81 (400 MHz, DMSO-d₆) δ ppm 0.07 (d, J = 3.54 Hz, 7H) 0.39 (d, J = 7.07 Hz, 8 H) 1.06 (br. s., 4 H) 1.39 (br. s., 1 H) 1.44(s, 36 H) 2.84 (d, J = 7.07 Hz, 8 H) 7.10 (s, 4 H) 7.16 (d, J = 5.05 Hz,4 H) 7.78 (d, J = 6.57 Hz, 8 H) 8.35 (d, J = 6.57 Hz. 8 H) 8.44 (s, 4 H)8.58 (d, J = 5.05 Hz, 4 H) 10.08 (s, 4H) 10j

M + 1 = 378.2050 4.23 (400 MHz, DMSO-d₆) δ ppm 0.01- 0.13 (m, 2 H) 0.36(d, J = 6.57 Hz, 2 H) 0.87-1.14 (m, 4 H) 2.82 (d, J = 6.57 Hz, 2 H) 3.85(d, J = 5.05 Hz, 1 H) 4.70 (d, J = 5.05 Hz, 1 H) 7.15 (d, J = 5.56 Hz, 1H) 7.36 (t, J = 5.81 Hz, 1 H) 7.77 (d, J = 6.57 Hz, 2 H) 8.35 (d, J =6.06 Hz, 2 H) 8.44 (s, 1 H) 8.59 (d, J = 5.05 Hz, 1 H) 10.06 (s, 1 H)10k

M + 1 = 378.2038 5.92 (400 MHz, MeOD) δ ppm 0.09 (d, J = 5.05 Hz, 2 H)0.33-0.48 (m, 2 H 1.06 (d, J = 6.06 Hz, 1 H) 1.22 (d, J = 6.06 Hz, 3 H)2.88 (d, J = 7.07 Hz, 2 H) 3.39 (dd, J = 13.64, 7.07 Hz, 1 H) 3.54 (dd,J = 13.64, 4.55 Hz, 1 H) 3.92-4.10 (m, 1 H) 7.09 (d, J = 5.05 Hz, 1 H)7.83 (d, J = 6.57 Hz, 2 H) 8.30 (d, J = 6.57 Hz, 2 H) 8.43 (s, 1 H) 8.55(d, J = 5.05 Hz, 1 H) 10l

M + 1 = 378.2048 2.86 (400 MHz, MeOD) δ ppm 0.09 (d, J = 5.05 Hz, 2 H)0.34-0.49 (m, 2 H) 1.06 (d, J = 6.06 Hz, 1 H) 1.22 (d, J = 6.57 Hz, 3 H)2.88 (d, J = 7.07 Hz, 2 H) 3.33-3.45 (m, 2 H) 3.50-3.63 (m, 1 H)3.90-4.09 (m, 1 H) 7.10 (d, J = 5.05 Hz, 1 H) 7.83 (d, J = 6.57 Hz, 2 H)8.30 (d, J = 6.57 Hz, 2 H) 8.43 (s, 1 H) 8.56 (d, J = 5.56 Hz, 1 H) 10m

M + 1 = 364.1884 2.70 (400 MHz, MeOD) δ ppm 0.05- 0.17 (m, 2 H)0.35-0.49 (m, 2 H) 1.06 (d, J = 5.05 Hz, 1 H) 2.89 (d, J = 7.07 Hz, 2 H)3.60 (t, J = 5.81 Hz, 2 H) 3.75 (t, J = 5.81 Hz, 2 H) 7.10 (d, J = 5.05Hz, 1 H) 7.83 (d, J = 6.57 Hz, 2 H) 8.30 (d, J = 6.57 Hz, 2 H) 8.44 (s,1 H) 8.56 (d, J = 5.05 Hz, 1 H) 10n

M + 1 = 378.2036 4.85 (400 MHz, DMSO-d₆) δ ppm 0.03 (br. s., 2 H) 0.36(br. s., 2H) 0.90- 1.11 (m, 1 H) 2.82 (d, J = 6.53 Hz, 2 H) 3.23-3.30(m, 3 H) 3.50 (br. s., 4 H) 7.16 (d, J = 5.52 Hz, 1 H) 7.47- 7.59 (m, 1H) 7.77 (d, J = 6.02 Hz, 2 H) 8.30-8.40 (m, 2 H) 8.45 (s, 1 H) 8.59 (d,J = 5.02 Hz, 1 H) 10.11 (s, 1 H) 10o

M + 1 = 378.2051 4.44 (400 MHz, DMSO-d₆) δ ppm 0.03 (d, J = 5.52 Hz, 2H) 0.15 (s, 2 H) 0.36 (d, J = 6.02 Hz, 1 H) 1.00 (d, J = 5.52 Hz, 1 H)1.16 (d, J = 6.53 Hz, 3 H) 2.82 (d, J = 6.53 Hz, 2 H) 3.44- 3.59 (m, 1H) 3.98-4.16 (m, 1 H) 4.71 (t, J = 5.77 Hz, 1 H) 7.16 (d, J = 5.02 Hz, 1H) 7.77 (d, J = 6.53 Hz, 2 H) 8.35 (d, J = 6.02 Hz, 2 H) 8.44 (s, 1H)8.59 (d, J = 5.02 Hz, 1 H) 10.10 (s, 1 H) 10p

M + 1 = 378.2044 5.99 (400 MHz, DMSO-d₆) δ ppm 0.01- 0.13 (m, 2 H)0.36(d, J = 7.58 Hz, 2 H) 0.92-1.06 (m, 1 H) 1.16 (d, J = 6.57 Hz, 3 H) 2.82(d, J = 7.07 Hz, 2 H) 3.33-3.44 (m, 1 H) 3.44-3.60 (m, 1 H) 3.95-4.15(m, 1 H) 4.68 (t, J = 5.81 Hz, 1 H) 7.09-7.24 (m, 2 H) 7.77 (d, J = 6.57Hz, 2 H) 8.35 (d, J = 6.57 Hz, 2 H) 8.44 (s, 1 H) 8.58 (d, J = 5.05 Hz,1 H) 10.06 (s, 1 H) 10q

M + 1 = 378.2056 5.98 (400 MHz, DMSO-d₆) δ ppm 0.00- 0.14 (m, 2 H) 0.36(d, J = 7.07 Hz, 2 H) 0.93-1.06 (m, 1 H) 1.16 (d, J = 6.57 Hz, 3 H) 2.82(d, J = 7.07 Hz, 2 H) 3.32-3.39 (m, 1 H) 3.52 (d, J = 5.05 Hz, 1 H)3.95-4.14 (m, 1 H) 4.68 (t, J = 5.81 Hz, 1 H) 7.09-7.26 (m, 2 H) 7.77(d, J = 6.57 Hz, 2 H) 8.35 (d, J = 6.57 Hz, 2 H) 8.44 (s, 1 H) 8.58 (d,J = 5.05 Hz, 1 H) 10.06 (s, 1 H) 10r

M + 1 = 390.2398 3.89 (400 MHz, DMSO-d₆) δ ppm 0.07 (br. s., 2 H) 0.36(br. s., 2 H) 0.92 (s, 9 H) 1.07 (br. s., 1 H) 2.83 (d, J = 7.03 Hz, 2H) 3.27 (br. s., 2 H) 7.16 (d, J = 5.02 Hz, 1 H) 7.55 (br. s., 1 H) 7.77(d, J = 6.53 Hz, 2 H) 8.35 (d, J = 6.02 Hz, 2 H) 8.43 (s, 1 H) 8.58 (d,J = 5.02 Hz, 1 H) 10.09 (s, 1 H) 10s

M + 1 = 376.2258 3.65 (400 MHz, DMSO-d₆) δ ppm 0.15 (s, 2 H) 0.36 (br.s., 2 H) 0.89 (t, J = 7.28 Hz, 3 H) 1.04 (br. s., 1 H) 1.15 (d, J = 6.02Hz, 3 H) 1.41-1.70 (m, 2 H) 2.75-2.90 (m, 2 H) 3.97 (br. s., 1 H) 7.16(d, J = 5.02 Hz, 1 H) 7.40 (br. s., 1 H) 7.78 (d, J = 6.53 Hz, 2 H) 8.36(d, J = 6.02 Hz, 2 H) 8.43 (s, 1 H) 8.59 (d, J = 5.02 Hz, 1 H) 10.11 (s,1 H) 10t

M + 1 = 392.2211 3.02 (400 MHz, MeOD) δ ppm 0.02- 0.18 (m, 2 H)0.33-0.50 (m, 2 H) 0.97-1.14 (m, 1 H) 1.25 (s, 6 H) 2.89 (d, J = 7.07Hz, 2 H) 3.52 (s, 2 H) 7.10 (d, J = 5.56 Hz, 1 H) 7.83 (d, J = 6.57 Hz,2 H) 8.30 (d, J = 6.57 Hz, 2 H) 8.44(s, 1 H) 8.56 (d, J = 5.05 Hz, 1 H)10u

M + 1 = 335.1621 2.96 (400 MHz, MeOD) δ ppm 0.09- 0.14 (m, 2 H)0.40-0.46 (m, 2 H) 1.03-1.13 (m, 1 H) 2.94 (d, J = 7.07 Hz, 2 H) 4.09(s, 3 H) 7.16 (d, J = 5.05 Hz, 1 H) 7.83 (d, J = 7.07 Hz, 2 H) 8.30 (d,J = 7.07 Hz, 2 H) 8.63 (d, J = 5.05 Hz, 1 H) 8.65 (s, 1 H) 10v

M + 1 = 305.1513 2.50 (400 MHz, CDCl3) δ ppm 0.12- 0.18 (m, 2 H)0.45-0.52 (m, 2 H) 1.06-1.17 (m, 1 H) 2.92 (d, J = 7.07 Hz, 2H) 7.02 (d,J = 5.05 Hz, 1 H) 7.60 (s, 1 H) 7.65 (d, J = 6.06 Hz, 2 H) 8.49 (s, 2 H)8.65 (d, J = 5.05 Hz, 1 H) 8.76 (s, 1 H) 9.25 (s, 1 H)

Example 11 Preparation of4′-(Cyclopropylmethyl)-2′-(methylsulfanyl)-N-pyridin-4-yl-4,5′-bipyrimidin-2-amine(11)

To a solution of(Z)-1-cyclopropyl-4-(dimethylamino)-3-(2-(pyridin-4-ylamino)pyrimidin-4-yl)but-3-en-2-one(9) (200 mg, 0.618 mmol) in DMF (5.154 ml) was added potassium carbonate(256 mg, 1.855 mmol) and 2-methyl-2-thiopseudourea sulfate (129 mg,0.928 mmol). The reaction was warmed to 120° C. and stirred for 1 hr.The solvent was evaporated and the crude residue partitioned between DCMand water. The organic layer was washed with brine, dried with sodiumsulfate, and concentrated. The crude product was purified by flashchromatography with a gradient of 2-10% MeOH in DCM and further purifiedreverse phase HPLC with a gradient of 10-100% MeCN in H2O to give 7.8 mgof the desired product as a white solid. HRMS (ES+)=351.1391. UV-LC:100/100% UV purity at 214/254 nm; HPLC: t_(R)=3.38 minute over 7.75minutes. 1H NMR (400 MHz, MeOD) δ ppm 0.10-0.14 (m, 2H) 0.41-0.47 (m,2H) 1.03-1.15 (m, 1H) 2.63 (s, 3H) 2.94 (d, J=7.07 Hz, 2H) 7.18 (d,J=5.56 Hz, 1H) 7.83 (d, J=7.07 Hz, 2H) 8.31 (d, J=7.07 Hz, 2H) 8.64 (s,1H) 8.65 (d, J=5.05 Hz, 1H)

Example 12a-12c General method for synthesis of4′-(cyclopropylmethyl)-N²-pyridin-4-yl-4,5′-bipyrimidine-2,2′-diamines12a-c Preparation of4′-Cyclopropylmethyl-N^(2′)-isopropyl-N²-pyridin-4-yl-[4,5′]bipyrimidinyl-2,2′-diamine(12a)

To a solution of4′-(cyclopropylmethyl)-2′-(methylsulfanyl)-N-pyridin-4-yl-4,5′-bipyrimidin-2-amine(11) (35 mg, 0.096 mmol) in DMSO (1 mL), isopropylamine (24.55 μl, 0.287mmol) was added and the reaction was microwaved for 20 minutes at 160°C. The crude product was purified by reverse-phase HPLC [30-100% organicphase over 15 minutes] followed by Biotage™ silica gel chromatography[10 g SNAP column, 100% DCM to 10% MeOH/DCM] to afford the titlecompound as a pale-yellow solid (13.67 mg, 39.6% yield). 1H NMR (400MHz, MeOD) δ ppm 0.04-0.17 (m, 2H) 0.31-0.50 (m, 2H) 0.97-1.17 (m, 1H)1.27 (d, J=6.57 Hz, 6H) 2.88 (d, J=7.07 Hz, 2H) 4.22 (ddd, J=13.01,6.44, 6.32 Hz, 1H) 7.10 (d, J=5.05 Hz, 1H) 7.84 (d, J=7.07 Hz, 2H) 8.30(d, J=6.57 Hz, 2H) 8.42 (s, 1H) 8.55 (d, J=5.05 Hz, 1H). HRMS (ES+) forC20H23N7.H⁺ [MH⁺]: calcd, 362.2093; found, 362.2083. UV-LC: 100% UVpurity at 254/214 nm; t_(R)=3.39 minutes over 7.75 minutes.

TABLE 6

Example R HRMS (ES+ m/z) HPLC t_(R) (min) 1H NMR 12a

M + 1 = 362.2083 3.39 (400 MHz, MeOD) δ ppm 0.04- 0.17 (m, 2 H)0.31-0.50 (m, 2 H) 0.97-1.17 (m, 1 H) 1.27 (d, J = 6.57 Hz, 6 H) 2.88(d, J = 7.07 Hz, 2 H) 4.22 (ddd, J = 13.01, 6.44, 6.32 Hz, 1 H) 7.10 (d,J = 5.05 Hz, 1 H) 7.84 (d, J = 7.07 Hz, 2 H) 8.30 (d, J = 6.57 Hz, 2 H)8.42 (s, 1 H) 8.55 (d, J = 5.05 Hz, 1 H) 12b

M + 1 = 402.2408 3.92 (400 MHz, MeOD) δ ppm 0.10 (d, J = 5.05 Hz, 2 H)0.32-0.49 (m, 2 H) 1.05 (d, J = 7.58 Hz, 1 H) 1.21-1.51 (m, 5 H) 1.67(br. s., 1 H) 1.75- 1.89 (m, 2 H) 1.98-2.11 (m, 2 H) 2.87 (d, J = 7.07Hz, 2 H) 3.88 (br. s., 1 H) 7.09 (d, J = 5.56 Hz, 1 H) 7.83 (d, J = 7.07Hz, 2 H) 8.30 (d, J = 6.57 Hz, 2 H) 8.41 (s, 1 H) 8.55 (d, J = 5.05 Hz,1 H) 12c

M + 1 = 360.1941 3.07 (400 MHz, MeOD) δ ppm 0.09 (q, J = 5.05 Hz, 2 H)0.35-0.45 (m, 2 H) 0.53-0.63 (m, 2 H) 0.75-0.85 (m, 2 H) 1.07 (t, J =7.07 Hz, 1 H) 2.80 (ddd, J = 6.95, 3.41, 3.28 Hz, 1 H) 2.89 (d, J = 6.57Hz, 2 H) 7.11 (d, J = 5.05 Hz, 1 H) 7.84 (d, J = 6.57 Hz, 2 H) 8.30 (d,J = 6.57 Hz, 2 H) 8.45 (s, 1 H) 8.57 (d, J = 5.05 Hz, 1 H)

Examples 16a-16g General Method for Synthesis of 16a-f Preparation of1-(2-(2-chloropyridin-4-ylamino)-4′-(cyclopropylmethyl)-4,5′-bipyrimidin-2′-ylamino)-2-methylpropan-2-ol(16a)

To a solution of 4-amino-2-chloropyridine (53.3 mg, 0.415 mmol) in THF(277 μl) cooled to −78° C. under nitrogen, LiHMDS (415 μl, 0.415 mmol)was added dropwise. The reaction mixture was warmed up to rt, then wasstirred for 30 minutes. To the reaction mixture cooled back to −78° C.,1-(4′-(cyclopropylmethyl)-2-(methylsulfinyl)-4,5′-bipyrimidin-2′-ylamino)-2-methylpropan-2-ol(5-3) (50 mg, 0.138 mmol) was added, and the reaction mixture was warmedup to rt, then was stirred for additional 1 hour. According to LC/MS,the reaction was complete. The crude product was purified byreverse-phase HPLC [30-100% organic phase over 15 minutes] followed byBiotage™ silica gel chromatography [10 g SNAP column, 100% DCM to 12%MeOH/DCM] to obtain the desired product (29 mg, 49%).

Preparation of4-(4′-(cyclopropylmethyl)-2′-(2-hydroxy-2-methylpropylamino)-4,5′-bipyrimidin-2-ylamino)benzonitrile(16b)

To a solution of 4-aminobenzonitrile (16.34 mg, 0.138 mmol) in THF (277μl) cooled to −78° C. under nitrogen, LiHMDS (415 μl, 0.415 mmol) wasadded dropwise. The reaction mixture was warmed up to rt, then wasstirred for 30 minutes. To the reaction mixture cooled back to −78° C.,1-(4′-(cyclopropylmethyl)-2-(methylsulfinyl)-4,5′-bipyrimidin-2′-ylamino)-2-methylpropan-2-ol(5-3) (50 mg, 0.138 mmol) was added, and the reaction mixture was warmedup to rt, then was stirred for additional 1 hour. According to LC/MS,the reaction was complete. The crude product was purified byreverse-phase HPLC [30-100% organic phase over 15 minutes] followed byBiotage™ silica gel chromatography [10 g SNAP column, 100% DCM to 12%MeOH/DCM] to obtain the desired product (16 mg, 28%).

Preparation of1-(4′-(cyclopropylmethyl)-2-(4-(methylsulfonyl)phenylamino)-4,5′-bipyrimidin-2′-ylamino)-2-methylpropan-2-ol(16d)

To a solution of 4-sulfonylaniline (71.1 mg, 0.415 mmol) in THF (277 μl)cooled to −78° C. under nitrogen, LiHMDS (69.4 mg, 0.415 mmol) was addeddropwise. The reaction mixture was warmed up to rt, then was stirred for30 minutes. To the reaction mixture cooled back to −78° C.,1-(4′-(cyclopropylmethyl)-2-(methylsulfinyl)-4,5′-bipyrimidin-2′-ylamino)-2-methylpropan-2-ol(5-3) (50 mg, 0.138 mmol) was added, and the reaction mixture was warmedup to rt, then was stirred for additional 1 hour. According to LC/MS,the reaction was complete. The crude product was purified byreverse-phase HPLC [30-100% organic phase over 15 minutes] followed byBiotage™ silica gel chromatography [10 g SNAP column, 100% DCM to 12%MeOH/DCM] to obtain the desired product (11 mg, 17%).

The compounds listed in Table 7 below were prepared using the proceduresas indicated above using the appropriate starting materials.

TABLE 7

HPLC t_(R) Example R HRMS (ES+ m/z) (min) 1H NMR 16a

M + 1 = 426.1819 5.57 (400 MHz, DMSO-d₆) δ ppm 0.05 (br. s., 2 H) 0.37(d, J = 6.57 Hz, 2 H) 0.97 (br. s., 1 H) 1.08 (d, J = 7.07 Hz, 1 H) 1.13(s, 7 H) 2.83 (d, J = 7.07 Hz, 2 H) 3.39 (d, J = 3.54 Hz, 2 H) 4.57 (s,1 H) 7.17 (br. s., 1 H) 7.23 (d, J = 5.05 Hz, 2 H) 7.64-7.73 (m, 1 H)8.01 (s, 1 H) 8.17 (d, J = 5.56 Hz, 1 H) 8.45 (s, 1 H) 8.63 (d, J = 5.05Hz, 1 H) 10.35 (s, 1 H) 16b

M + 1 = 416.2200 5.71 (400 MHz, DMSO-d₆) δ ppm 0.04 (br. s., 2 H) 0.35(d, J = 7.07 Hz, 2 H) 0.99 (d, J = 14.15 Hz, 1 H) 1.13 (s, 6 H) 2.81 (d,J = 6.57 Hz, 2 H) 3.38 (d, J = 5.56 Hz, 2 H) 4.57 (br. s., 1 H) 7.15 (d,J = 5.05 Hz, 1 H) 7.22 (br. s., 1 H) 7.73 (m, J = 9.09 Hz, 2 H) 7.98 (m,J = 8.59 Hz, 2 H) 8.43 (s, 1 H) 8.58 (d, J = 5.05 Hz, 1 H) 10.17 (s, 1H) 16c

M +1 = 409.2154 6.09 (400 MHz, DMSO-d₆) δ ppm 0.04 (br. s., 2 H) 0.35(d, J = 7.07 Hz, 2 H) 0.89-1.07 (m, 1 H) 1.12 (s, 6 H) 2.79 (d, J = 6.57Hz, 2 H) 3.37 (d, J = 5.56 Hz, 2 H) 4.57 (br. s., 1 H) 6.99 (d, J = 5.05Hz, 1 H) 7.12 (t, J = 8.84 Hz, 2 H) 7.14-7.22 (m, 1 H) 7.74 (dd, J =9.09, 5.05 Hz, 2 H) 8.40 (s, 1 H) 8.47 (d, J = 5.05 Hz, 1 H) 9.59 (s, 1H) 16d

M + 1 = 469.2026 5.01 (400 MHz, MeOD) δ ppm 0.09 (d, J = 4.55 Hz, 2 H)0.36-0.48 (m, 2 H) 1.08 (d, J = 13.14 Hz, 1 H) 1.21-1.30 (m, 6 H) 2.88(d, J = 6.57 Hz, 2 H) 3.05-3.13 (m, 3 H) 3.52 (s, 2 H) 7.06 (d, J = 5.56Hz, 1 H) 7.84 (m, J = 8.59 Hz, 2 H) 8.01 (m, J = 9.09 Hz, 2 H) 8.44 (s,1 H) 8.53 (d, J = 5.05 Hz, 1 H) 16e

M + 1 = 425.1857 6.47 (400 MHz, MeOD) δ ppm 0.02- 0.15 (m, 2 H)0.29-0.51 (m, 2 H) 0.96-1.16 (m, 1 H) 1.16- 1.34 (m, 6 H) 2.85 (d, J =7.07 Hz, 2 H) 3.51 (s, 2 H) 6.94 (d, J = 5.05 Hz, 1 H) 7.26 (m, J = 8.59Hz, 2 H) 7.68 (m, J = 9.09 Hz, 2 H) 8.40 (s, 1 H) 8.43 (d, J = 5.56 Hz,1 H) 16f

M + 1 = 448.2443 4.41 (400 MHz, DMSO-d₆) δ ppm 0.06 (d, J = 2.53 Hz, 2H) 0.36 (d, J = 7.58 Hz, 2 H) 1.13 (s, 6 H) 2.01 (s, 3 H) 2.82 (d, J =7.07 Hz, 2 H) 3.38 (br. s., 2 H) 6.97 (d, J = 5.05 Hz, 1 H) 7.27 (d, J =8.59 Hz, 1 H) 7.47 (d, J = 9.09 Hz, 2 H) 7.61 (d, J = 8.59 Hz, 2 H) 8.43(s, 1 H) 8.45 (d, J = 5.05 Hz, 1 H) 9.50 (s, 1 H) 9.80 (s, 1 H) 16g

M + 1 = 490.2603 3.82 (400 MHz, DMSO-d₆) δ ppm 0.13 (d, J = 10.61 Hz, 2H) 0.39 (d, J = 7.07 Hz, 2 H) 0.96-1.17 (m, 8 H) 1.19-1.47 (m, 4 H) 1.92(d, J = 10.11 Hz, 4 H) 2.80 (br. s., 2 H) 2.91 (s, 3 H) 3.08 (d, J =2.02 Hz, 1 H) 3.67 (br. s., 1 H) 4.58 (br. s., 1 H) 6.71 (d, J = 5.05Hz, 1 H) 6.93-7.19 (m, 3 H) 8.25 (d, J = 5.05 Hz, 1 H) 8.36 (br. s., 1H)

Preparation of intermediate1-(2-Methylsulfanyl-pyrimidin-4-yl)-propan-2-one (17)

To a solution of 4-Methyl-2-(methylthio)pyrimidine (1) (3 g, 21.40 mmol)in THF (35.7 mL) at −10° C. was added LHMDS (32.1 mL, 32.1 mmol, 1M inTHF). The resulting reaction was warmed to rt and stirred for 15minutes, after which time the reaction was cooled back to −10° C. andBenzyl Acetate (3.21 mL, 23.54 mmol) was added. The reaction was thenwarmed to rt and stirred for 1 hour, after which time completeconversion to product was observed by LCMS. TLC after 1 hour stillshowed the presence of some starting material and the reaction wascontinued stirring for an additional hour. After this time there was nochange in TLC and the reaction was worked up. The reaction was quenchedby slow addition of saturated ammonium chloride and the volatile solventevaporated. The mixture was then diluted with EtOAc and water. Theorganic layer was then washed with brine, dried with sodium sulfate, andconcentrated. The crude residue was purified by flash chromatographywith a gradient of 8-66% EtOAc in Heptane to give the desired product asa yellow liquid (1.93 g, 50%). MS (ES+): m/z=183.1 (100) [MH⁺]. HPLC:t_(R)=0.91 minute over 3 minutes. Purity: 76% [HPLC (LC/MS) at 220 nm].

Preparation of intermediate4-Dimethylamino-3-(2-methylsulfanyl-pyrimidin-4-yl)-but-3-en-2-one (18)

1-(2-Methylsulfanyl-pyrimidin-4-yl)-propan-2-one (17) (1.93 g, 10.59mmol) was taken up in DMF-DMA (20 mL, 149 mmol) and the resultingreaction was warmed to 80° C. and stirred for 2 hours. The solvent wasevaporated and the crude residue partitioned between DCM and water. Theorganic layer was washed with brine, dried with sodium sulfate, andconcentrated. The crude residue was purified by flash columnchromatography with a gradient of 1-12% MeOH in DCM to give the desiredproduct as a brown/orange oil (1.24 g, 49%). MS (ES+): m/z=238.2/239.3(100/30) [MH⁺]. HPLC: t_(R)=0.78 minute over 3 minutes. Purity: 100%[HPLC (LC/MS) at 220 nm].

Preparation of intermediate4′-Methyl-2-methylsulfanyl-[4,5′]bipyrimidinyl-2′-ylamine (19)

To a solution of4-Dimethylamino-3-(2-methylsulfanyl-pyrimidin-4-yl)-but-3-en-2-one (18)(1.02 g, 4.30 mmol) in DMF (14 mL) was added K₂CO₃ (1.782 g, 12.89 mmol)and Guanidine HCl (0.616 g, 6.45 mmol) and the resulting suspension wasstirred at 120° C. for 1 hour. The DMF was evaporated and the cruderesidue partitioned between water and ethyl acetate. The organic layerwas washed with water and brine, dried with sodium sulfate, andconcentrated. The crude residue was purified by flash chromatographywith a gradient of 1-12% MeOH in DCM to give the desired product as alight yellow solid (800 mg, 80%). MS (ES+): m/z=234.3/235.4 (100/20)[MH⁺]. HPLC: t_(R)=1.01 minutes over 3 minutes. Purity: 70% [HPLC(LC/MS) at 220 nm].

Preparation of intermediate2-Methanesulfinyl-4′-methyl-[4,5′]bipyrimidinyl-2′-ylamine (20)

To a suspension of4′-Methyl-2-methylsulfanyl-[4,5′]bipyrimidinyl-2′-ylamine (19) (380 mg,1.629 mmol) in DCM (3.258 mL) was added mCPBA (402 mg, 1.629 mmol). Thereaction turned to a brown solution, and immediately the reaction wascomplete. The reaction mixture was diluted with DCM and water. Theorganic layer was washed with saturated sodium bicarbonate and brine,dried with sodium sulfate, and concentrated. The crude residue waspurified by flash chromatography with a gradient of 2-10% MeOH in DCM togive the desired product (70 mg, 17%). MS (ES+): m/z=250.1 (100) [MH⁺].HPLC: t_(R)=0.64 minute over 3 minutes.

Example 21 Preparation of4′-Methyl-N²-pyridin-4-yl-[4,5′]bipyrimidinyl-2,2′-diamine (21)

To a solution of 4-aminopyridine (423 mg, 4.49 mmol) in THF (0.562 mL)cooled to −10° C. was added LHMDS (1M in THF) (1.123 mL, 1.123 mmol).The resulting suspension was warmed to rt and stirred for 15 minutes,after which time it was cooled back to −10° C. and2-Methanesulfinyl-4′-methyl-[4,5′]bipyrimidinyl-2′-ylamine (20) (70 mg,0.281 mmol) was then added. The reaction mixture was again warmed to rtand stirred for 1.5 hours. The reaction was quenched by slow addition ofsaturated ammonium chloride and the volatiles evaporated. The mixturewas then diluted with DCM, the layers separated, and the organic layerwashed with brine, dried with sodium sulfate, and concentrated. Thecrude residue was purified by flash column chromatography with agradient of 2-20% MeOH in DCM. The product was further purified byreverse phase HPLC with a gradient of 10-90% MeCN in water over 15minutes, to give the desired product as a white solid (1.39 mg, 0.44%).1H NMR (400 MHz, MeOD) δ ppm 2.57 (s, 3H) 7.13 (d, J=5.56 Hz, 1H) 7.84(d, J=6.57 Hz, 2H) 8.30 (d, J=6.57 Hz, 2H) 8.50 (s, 1H) 8.57 (d, J=5.05Hz, 1H). HRMS (ES+) for C14H13N7.H⁺ [MH⁺]: calcd, 280.1311; found,280.1318. UV-LC: 100/100% UV purity at 214/254 nm; t_(R)=2.93 minutesover 7.75 minutes.

Example 22 Preparation ofN2-(pyridin-4-yl)-4′-(trifluoromethyl)-4,5′-bipyrimidine-2,2′-diamine(22)

This compound was synthesized in an analogous manner to 21 utilizingbenzyl 2,2,2-trifluoroacetate in step 1. To a solution of4-aminopyridine (17.38 mg, 0.185 mmol) in THF (92 μl) cooled to −78° C.under nitrogen, LiHMDS (852 μl, 0.852 mmol) was added dropwise. Thereaction mixture was warmed up to rt, then was stirred for 30 minutes.To the reaction mixture cooled back to −78° C.,2-(methylsulfinyl)-4′-(trifluoromethyl)-4,5′-bipyrimidin-2′-amine (14mg, 0.046 mmol) was added, and the reaction mixture was warmed up to rt,then was stirred for 1 hour. The crude product was purified byreverse-phase HPLC [30-100% organic phase over 15 minutes] followed byBiotage™ silica gel chromatography [10 g SNAP column, 100% DCM to 12%MeOH/DCM] to obtain the desired product as a pale yellow solid (3.98 mg,25% yield). 1H NMR (400 MHz, DMSO-d₆) δ ppm 7.13 (d, J=4.52 Hz, 1H) 7.67(br. s., 2H) 7.77 (d, J=6.02 Hz, 2H) 8.34 (d, J=6.02 Hz, 2H) 8.56-8.74(m, 2H) 10.23 (s, 1H). HRMS (ES+) for C14H10F3N7.H⁺ [MH⁺]: calcd,334.1028; found, 334.1037. UV-LC: 97.31/100% UV purity at 214/254 nm;t_(R)=2.47 minutes over 7.75 minutes.

Example 13 Preparation of4′-Benzyloxymethyl-N²-pyridin-4-yl-[4,5′]bipyrimidinyl-2,2′-diamine (13)

This compound was synthesized in an analogous manner to compound 21utilizing 2-(benzyloxy)-N-methoxy-N-methylacetamide in step one. To asolution of 4-aminopyridine (79 mg, 0.836 mmol) in THF (1114 μl) cooledto −78° C. was added LHMDS (836 μl, 0.836 mmol). The reaction wasstirred −78° C. for 15 minutes, after which time4′-(benzyloxymethyl)-2-(methylsulfinyl)-4,5′-bipyrimidin-2′-amine (99mg, 0.279 mmol) was added as a solution in THF (2 mL). The reaction waswarmed to rt and stirred for 1 hour. The reaction was quenched by slowaddition of saturated ammonium chloride and the reaction mixture wasdiluted with EtOAc. The residue was then partitioned between water andEtOAc. The organic layer was washed with brine, dried with sodiumsulfate, and concentrated in vacuo. The crude product was purified byreverse-phase HPLC [30-100% organic phase over 15 minutes] followed byBiotage™ silica gel chromatography [10 g SNAP column, 100% DCM to 10%MeOH/DCM] to obtain the desired product as a pale yellow solid (94 mg,88% yield). 1H NMR (400 MHz, DMSO-d₆) δ ppm 4.42 (s, 2H) 4.68 (s, 2H)7.07-7.19 (m, 4H) 7.19-7.31 (m, 4H) 7.76 (d, J=6.57 Hz, 2H) 8.34 (d,J=6.06 Hz, 2H) 8.50-8.64 (m, 2H) 10.05 (s, 1H). HRMS (ES+) forC21H19N7O.H⁺ [MH⁺]: calculated, 386.1729; found, 386.1731. UV-LC:100/100% UV purity at 214/254 nm; t_(R)=2.78 minutes over 7.75 minutes.

Example 23 Preparation of[2′-Amino-2-(pyridin-4-ylamino)-4,5′-bipyrimidin-4′-yl]methanol (23)

This compound was synthesized in an analogous manner to 21 utilizingbenzyl 2-(tert-butyldiphenylsilyloxy)acetate in step one, and furtherTBDPS deprotection as the last step. To4′-(tert-Butyl-diphenyl-silanyloxymethyl)-N²-pyridin-4-yl-[4,5′]bipyrimidinyl-2,2′-diamine(150 mg, 0.281 mmol), TBAF (1N in THF) (562 μl, 0.562 mmol) was added.The reaction was stirred rt for 1 hour. Additional TBAF (1N in THF) (281μl, 0.281 mmol) was added, and the reaction mixture was stirred for anadditional 2 hours. The reaction was quenched by slow addition ofsaturated ammonium chloride and the volatiles were evaporated. Theresidue was then partitioned between water and EtOAc. The organic layerwas washed with brine, dried with sodium sulfate, and concentrated. Thecrude product was purified by reverse-phase HPLC [100% aqueous phase to60% organic phase over 15 minutes] to obtain the desired product as aslightly pale yellow solid (50 mg, 60% yield). 1H NMR (400 MHz, DMSO-d₆)ppm 4.66 (d, J=2.53 Hz, 2H) 5.04 (br. s., 1H) 7.18 (s, 2H) 7.30 (d,J=5.05 Hz, 1H) 7.77 (d, J=6.06 Hz, 2H) 8.36 (d, J=6.06 Hz, 2H) 8.57 (d,J=5.56 Hz, 1H) 8.63 (s, 1H) 10.03 (s, 1H). HRMS (ES+) for C14H13N7O.H⁺[MH⁺]: calcd. 296.1260; found 296.1263. UV-LC: 100/100% UV purity at214/254 nm; t_(R)=2.87 minutes over 7.75 minutes

Example 24 Preparation of2-methyl-1-(2-(pyridin-4-ylamino)-4′-(trifluoromethyl)-4,5′-bipyrimidin-2′-ylamino)propan-2-ol(24)

This compound was synthesized in an analogous manner to 22 utilizing1-(2-hydroxy-2-methylpropyl)guanidine in step 3. To a solution of4-aminopyridine (80 mg, 0.852 mmol) in THF (426 μl) cooled at −78° C.under nitrogen, LiHMDS (852 μl, 0.852 mmol) was added dropwise. Thereaction mixture was warmed up to rt, then was stirred for 30 minutes.To the reaction mixture cooled back to −78° C.,2-methyl-1-(2-(methylsulfinyl)-4′-(trifluoromethyl)-4,5′-bipyrimidin-2′-ylamino)propan-2-ol(80 mg, 0.213 mmol) was added, and the reaction mixture was warmed up tort, then was stirred for 1 hour. The crude product was purified byreverse-phase HPLC [30-100% organic phase over 15 minutes] followed byBiotage™ silica gel chromatography [10 g SNAP column, 100% DCM to 12%MeOH/DCM] to obtain the desired product as a pale yellow solid (25.7 mg,30% yield). 1H NMR (400 MHz, DMSO-d₆) δ ppm 1.14 (s, 6H) 3.40 (br. s.,2H) 4.51 (s, 1H) 7.13 (d, J=5.05 Hz, 1H) 7.76 (s, 2H) 8.01 (br. s., 1H)8.34 (d, J=5.56 Hz, 2H) 8.66 (d, J=4.93 Hz, 1H) 10.19 (s, 1H). HRMS(ES+) for C18H18F3N7O.H⁺ [MH⁺]: calcd, 406.1603; found, 406.1612. UV-LC:100/100% UV purity at 214/254 nm; t_(R)=2.95 minutes over 7.75 minutes.

Example 25 Preparation of4-(2′-(2-hydroxy-2-methylpropylamino)-4′-(trifluoromethyl)-4,5′-bipyrimidin-2-ylamino)benzonitrile(25)

This compound was synthesized in an analogous manner to 24 utilizing4-aminobenzonitrile in step 5. A pale yellow solid (14.5 mg, 13% yield).1H NMR (400 MHz, DMSO-d₆) δ ppm 1.14 (s, 6H) 3.39 (dd, J=14.65, 5.56 Hz,2H) 4.53 (d, J=19.20 Hz, 1H) 7.12 (d, J=5.05 Hz, 1H) 7.72 (d, J=9.09 Hz,2H) 7.89-8.07 (m, 3H) 8.65 (d, J=5.05 Hz, 1H) 8.69 (br. s., 1H) 10.29(s, 1H). HRMS (ES+) for C20H18F3N7O.H⁺ [MH⁺]: calcd, 430.1603; found,430.1622. UV-LC: 100/98.09% UV purity at 214/254 nm; t_(R)=5.76 minutesover 7.75 minutes.

Example 27 Preparation of intermediateN′-{5-[(2E)-3-(dimethylamino)prop-2-enoyl]-4-methylpyrimidin-2-yl}-N,N-dimethylimidoformamide(27)

A solution of 5-acetyl-2-Amino-4-methypyrimidine (Alfa Aesar) (1.00 g,6.62 mmol) in DMF-DMA (35.4 mL, 265 mmol) was heated at 120° C. for 18hours. The reaction mixture was concentrated in vacuo, then was purifiedby Biotage™ silica gel chromatography [50 g SNAP column, 2-10% MeOH/DCM]to obtain a pale yellow solid as the desired product, which was driedover high vacuum for 1 hour (1.06 g, 61% yield). 1H NMR (400 MHz,DMSO-d₆) δ ppm 2.42 (s, 3H) 2.86 (br. s., 3H) 3.03 (s, 3H) 3.10 (br. s.,3H) 3.13 (s, 3H) 5.40 (d, J=12.63 Hz, 1H) 7.50 (d, J=12.63 Hz, 1H) 8.48(s, 1H) 8.64 (s, 1H).

Preparation of intermediateN²-(4-fluorophenyl)-4′-methyl-4,5′-bipyrimidinyl-2,2′-diamine (28)

A solution ofN′-{5-[(2E)-3-(dimethylamino)prop-2-enoyl]-4-methylpyrimidin-2-yl}-N,N-dimethylimidoformamide(27) (50 mg, 0.191 mmol), 1-(4-fluorophenyl)guanidine hydrochloride (102mg, 0.383 mmol), and K₂CO₃ (106 mg, 0.765 mmol) in DMF (1018 μl) washeated at 120° C. for 2 d. The crude product was filtered through asyringe filter, then the crude product was purified by reverse-phaseHPLC [30-100% organic phase over 15 minutes] to obtain ˜80% pure desiredproduct. The product was taken up in 10% MeOH/DCM, then was purified byBiotage™ silica gel chromatography [10 g SNAP column, 2-10% MeOH/DCM]and further purified by trituration with acetone and acetonitrile toobtain the desired product as a pale yellow solid (10.23 mg, 18% yield).1H NMR (400 MHz, DMSO-d₆) δ ppm 2.47 (s, 3H) 6.93 (s, 2H) 7.02 (d,J=5.05 Hz, 1H) 7.12 (t, J=8.84 Hz, 2H) 7.77 (dd, J=9.35, 4.80 Hz, 2H)8.44 (s, 1H) 8.46 (d, J=5.05 Hz, 1H) 9.61 (s, 1H). HRMS (ES+) forC15H13FN6.H⁺ [MH⁺]: calcd, 297.1264; found, 297.1274. UV-LC: 98.95/100%UV purity at 214/254 nm; t_(R)=4.30 minutes over 7.75 minutes.

Example 30 Preparation of intermediate2-chloro-4,5′-bipyrimidin-2′-amine (30)

A suspension of 2-aminopyrimidinylboronic ester (500 mg, 2.262 mmol)(Maybridge), 2,4-Dichloropyrimidine (337 mg, 2.262 mmol), and sodiumcarbonate (479 mg, 4.52 mmol) in a 10:1 mixture of DME (9047 μl) andwater (2262 μl) was degassed with nitrogen for 15 min, thenPdCl₂(dppf).CH₂Cl₂ adduct (185 mg, 0.226 mmol) was added. The reactionmixture was heated at 85° C. for 78 hours. The reaction mixture wasconcentrated in vacuo, then the resulting bright red residue was takenup in EtOAc, filtered through a syringe filter, then concentrated invacuo. The crude product was taken up in DCM, then was purified byBiotage™ silica gel chromatography [25 g SNAP column, 100% DCM to 20%MeOH/DCM] to obtain the desired product (110 mg, 23% yield). 1H NMR (400MHz, DMSO-d₆) δ ppm 7.47 (s, 2H) 8.02 (d, J=5.56 Hz, 1H) 8.69 (d, J=5.56Hz, 1H) 9.02 (s, 2H). MS (ES+): m/z=208.2 (100/80) [MH⁺]. HPLC:t_(R)=0.75 minute over 3 minutes. Purity: 100% [HPLC (LC/MS) at 220 nm].

Preparation of N2-(4-fluorophenyl)-4,5′-bipyrimidine-2,2′-diamine (31)

To a suspension of 2-chloro-4,5′-bipyrimidin-2′-amine (30) (110 mg,0.530 mmol) in THF (5298 μl), 4-Fluoroaniline (100 μl, 1.060 mmol) wasadded. DMSO (1 mL) was added to dissolve the starting chloride, and thesuspension was heated to 150° C. in the microwave for 2 hours. The crudereaction mixture was filtered through a syringe filter, then purified byreverse-phase HPLC [30-100% organic phase over 15 minutes] to obtain areddish purple product. The product was triturated with acetone andacetonitrile, then filtered to obtain a slightly gray solid as thedesired product (19 mg, 13% yield). 1H NMR (400 MHz, DMSO-d₆) δ ppm 7.15(t, J=9.09 Hz, 2H) 7.22 (s, 2H) 7.31 (d, J=5.05 Hz, 1H) 7.79 (dd,J=9.09, 5.05 Hz, 2H) 8.44 (d, J=5.05 Hz, 1H) 8.99 (s, 2H) 9.59 (s, 1H).HRMS (ES+) for C14H11FN6.H⁺ [MH⁺]: calcd, 283.1107; found, 283.1108.UV-LC: 100/100% UV purity at 214/254 nm; t_(R)=1.07 minutes over 7.75minutes.

Example 33 Preparation of intermediate5-acetyl-2-(methylthio)pyrimidin-4(3H)-one (33)

5-Acetyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (Ryan Scientific) (2.3g, 13.51 mmol) was dissolved in NaOH (20.27 mL, 20.27 mmol), then MeI(0.894 mL, 14.30 mmol) was added to the reaction mixture while stirring.The reaction mixture was heated at 40° C. for 1.5 hours. Additional MeI(0.894 mL, 14.30 mmol) was added and the reaction was allowed to stir atrt for 18 hours. The reaction mixture was cooled with an ice-water bath,acidified to pH 6 with concentrated HCl solution, then the resultingprecipitate was filtered to obtain 1.72 g of the desired product (69%yield). 1H NMR (400 MHz, DMSO-d₆) δ ppm 2.49 (br. s., 6H) 8.35 (s, 1H)13.40 (br. s., 1H). MS (ES+): m/z=185.1 (100) [MH⁺]. HPLC: t_(R)=1.0minute over 3 minutes. Purity: >90% [HPLC (LC/MS) at 220 nm].

Preparation of intermediate4-(4-(2-(methylthio)-6-oxo-1,6-dihydropyrimidin-5-yl)pyrimidin-2-ylamino)benzonitrile(34)

5-Acetyl-2-(methylthio)pyrimidin-4(3H)-one (33) (1.094 g, 5.94 mmol) wasdissolved in 1-tert-butoxy-N,N,N′,N′-tetramethylmethanediamine (12.26mL, 59.4 mmol), then the reaction mixture was heated at 120° C. for 6hours. The reaction mixture was concentrated in vacuo, and dried overhigh vacuum for 1 hour. The crude intermediate was taken up in DMF (31.6mL), then 1-(4-cyanophenyl)guanidine (2.076 g, 8.91 mmol) and K₂CO₃(4.10 g, 29.7 mmol) were added. The reaction mixture was heated at 120°C. for 48 hours. Additional 1-(4-cyanophenyl)guanidine (2.076 g, 8.91mmol) and K₂CO₃ (3.69 g, 26.7 mmol) were added, and the reaction mixturewas stirred at 120° C. for additional 18 hours. The reaction mixture wascooled to rt, then was slowly poured into an ice-cooled 1N HCl solutionwhile stirring vigorously. The reaction mixture was neutralized withadditional 1N HCl, then the reaction mixture was allowed to stir for anadditional 30 minutes. The resulting precipitate was filtered, washedmultiple times with DI water, 2-propanol, then diethyl ether. Theresulting crude product was dried over high vacuum for 18 hours toobtain the desired product as a red/brown solid (940 mg, 47% yield). MS(ES+): m/z=337.2 (100) [MH⁺]. HPLC: t_(R)=1.35 minutes over 3 minutes.Purity: 72% [HPLC (LC/MS) at 220 nm].

Example 35 Preparation of intermediate4-(4′-chloro-2′-(methylthio)-4,5′-bipyrimidin-2-ylamino)benzonitrile(35)

4-(4-(2-(Methylthio)-6-oxo-1,6-dihydropyrimidin-5-yl)pyrimidin-2-ylamino)benzonitrile(34) (700 mg, 2.081 mmol) was dissolved in POCl₃ (1940 μl, 20.81 mmol),then the reaction mixture was heated at 120° C. for 3 hours. Thereaction mixture was cooled to rt, then was slowly poured into anice-cooled saturated Na₂CO₃ solution while stirring vigorously. Thereaction mixture was then adjusted to pH 7 with additional Na₂CO₃solution. DCM was added to the mixture and the aqueous layer wasextracted twice with DCM. The organic extracts were combined, washedwith brine, dried over sodium sulfate, then concentrated in vacuo toobtain the desired product as a bright yellow solid (428 mg, 53% yield).1H NMR (400 MHz, DMSO-d₆) δ ppm 2.62 (s, 3H) 7.39 (d, J=5.05 Hz, 1H)7.74 (m, 2H) 8.00 (m, J=9.09 Hz, 2H) 8.69-8.80 (m, 1H) 8.93 (s, 1H)10.42 (s, 1H). MS (ES+): m/z=355.3 (100) [MH⁺]. HPLC: t_(R)=1.57 minutesover 3 minutes. Purity: 91% [HPLC (LC/MS) at 220 nm].

Example 36 Preparation of4-(4′-ethyl-2′-(methylthio)-4,5′-bipyrimidin-2-ylamino)benzonitrile(36a)

4-(4′-Chloro-2′-(methylthio)-4,5′-bipyrimidin-2-ylamino)benzonitrile(35) (205 mg, 0.526 mmol) and ferric acetylacetonate (18.57 mg, 0.053mmol) were dissolved in THF (3305 μl) and NMP (248 μl), thenethylmagnesium bromide (789 μl, 0.789 mmol) was added dropwise undernitrogen. The reaction was quenched with 1N HCl, then was extract withEtOAc. The organic extracts were combined, washed with brine, dried oversodium sulfate, then concentrated in vacuo. The crude product wasdry-loaded onto silica gel and purified by Biotage™ silica gelchromatography [25 g SNAP column, 30% EtOAc/heptane to 100% EtOAc] toobtain 49 mg of the desired product (21%). 1H NMR (400 MHz, DMSO-d₆) δppm 1.19 (t, J=7.58 Hz, 3H) 2.59 (s, 3H) 2.95 (q, J=7.58 Hz, 2H) 7.25(d, J=5.05 Hz, 1H) 7.68-7.78 (m, 2H) 7.95-8.03 (m, 2H) 8.67-8.75 (m, 2H)10.33 (s, 1H). MS (ES+): m/z=349.5 [M+1] (100). HPLC: t_(R)=1.57 minutesover 3 minutes. Purity: 93% [HPLC (LC/MS) at 220 nm].

Preparation of4-(4′-Isopropyl-2′-(methylthio)-4,5′-bipyrimidin-2-ylamino)benzonitrile(36b)

4-(4′-Chloro-2′-(methylthio)-4,5′-bipyrimidin-2-ylamino)benzonitrile(35) (125 mg, 0.352 mmol) and ferric acetylacetonate (12.44 mg, 0.035mmol) were dissolved in THF (1791 μl) and NMP (134 μl), thenisopropylmagnesium bromide (528 μl, 0.528 mmol) was added dropwise.According to LC/MS, approximately 40% conversion was observed.Additional isopropylmagnesium bromide (528 μl, 0.528 mmol) was added,and the reaction was stirred at rt for an additional 1 hour. Thereaction was quenched with 1N HCl, then was extract with EtOAc. Theorganic extracts were combined, washed with brine, dried over sodiumsulfate, then concentrated in vacuo. The crude product was dry-loadedonto silica gel, then was purified by Biotage™ silica gel chromatgraphy[25 g SNAP column, 30% EtOAc/heptane to 100% EtOAc] to obtain thedesired product (51.1 mg, 40%). MS (ES+): m/z=363.3 [M+1] (100). HPLC:t_(R)=1.70 minutes over 3 minutes.

Example 37 Preparation of4-(4′-ethyl-2′-(2-hydroxy-2-methylpropylamino)-4,5′-bipyrimidin-2-ylamino)benzonitrile(37a)

4-(4′-Ethyl-2′-(methylthio)-4,5′-bipyrimidin-2-ylamino)benzonitrile(36a) (48.6 mg, 0.112 mmol) and 1-amino-2-propanol (29.8 mg, 0.335 mmol)were dissolved in THF (540 μl) and NMP (54.0 μl), then the reactionmixture was microwaved at 150° C. for 1 hour. Additional1-amino-2-methylpropanol (99.8 mg, 1.12 mmol) was added, and thereaction mixture was microwaved further at 150° C. an additional 1 hour.Additional 1-amino-2-methylpropanol (99.8 mg, 1.12 mmol) was added, andthe reaction mixture was microwaved further at 200° C. The crudereaction mixture was purified by reverse-phase HPLC [30-100% organicphase over 15 minutes using 0.1% TFA modifier] followed by Biotage™silica gel chromatography [10 g SNAP column, 100% DCM to 10% MeOH/DCM]to obtain the desired product as a pale yellow solid (4.14 mg, 9%yield). 1H NMR (400 MHz, MeOD) δ ppm 1.20-1.27 (m, 9H) 2.94 (q, J=7.58Hz, 2H) 3.51 (s, 2H) 4.55 (s, 1H) 7.04 (d, J=5.56 Hz, 1H) 7.62 (m,J=9.09 Hz, 2H) 7.96 (m, J=8.59 Hz, 2H) 8.44 (s, 1H) 8.52 (d, J=5.05 Hz,1H). HRMS (ES+) for C21H23N7O.H⁺ [MH⁺]: calcd, 390.2042; found,390.2023. UV-LC: 96.40/95.08% UV purity at 214/254 nm; t_(R)=5.31minutes over 7.75 minutes.

4-(2′-(2-hydroxy-2-methylpropylamino)-4′-isopropyl-4,5′-bipyrimidin-2-ylamino)benzonitrile(37b)

4-(4′-Isopropyl-2′-(methylthio)-4,5′-bipyrimidin-2-ylamino)benzonitrile(36b) (51.1 mg, 0.141 mmol) and 1-amino-2-methylpropanol (126 mg, 1.410mmol) were dissolved in THF (513 μl) and NMP (51.3 μl), then thereaction mixture was microwaved at 200° C. for 2 hours. The reaction wasapproximately 10% complete. Additional 1-amino-2-methylpropanol (126 mg,1.410 mmol) was added, and the reaction mixture was microwaved at 200°C. for an additional 2 hours. The reaction mixture was microwaved at200° C. for additional 3.5 hours. The crude reaction mixture waspurified by reverse-phase HPLC [30-100% organic phase over 15 minutesusing 0.1% TFA modified mobile phase] to obtain the desired product as ayellow foamy solid. 1H NMR (400 MHz, MeOD) δ ppm 1.27 (d, J=6.57 Hz, 6H)1.30 (s, 6H) 3.43-3.65 (m, 2H) 3.71 (ddd, J=13.52, 6.69, 6.57 Hz, 1H)7.08 (d, J=5.05 Hz, 1H) 7.63 (m, J=9.09 Hz, 2H) 7.95 (m, J=8.59 Hz, 2H)8.45 (s, 1H) 8.61 (d, J=5.05 Hz, 1H). HRMS (ES+) for C22H25N7O.H⁺ [MH⁺]:calcd, 404.2199; found, 404.2201. UV-LC: 95.41/100% UV purity at 214/254nm; t_(R)=5.73 minutes over 7.75 minutes.

Biological Activity

Vps34 KinaseGlo assay: 50 nL of compound dilutions were dispensed ontoblack 384-well low volume Non Binding Styrene (NBS) plates (Costar Cat.No. NBS#3676). L-a-phosphatidylinositol (PI), provided as 10 mg/mLsolution in methanol (Avanti Polar Lipid; Cat. No. 840042C,Lot#LPI-274), was transferred into a glass tube and dried under nitrogenbeam. It was then resuspended in 3% OctylGlucoside by vortexing andstored at 4° C. 5 μL of a mix of PI/OG with recombinant human Vps34 wereadded.

Kinase reactions were started by addition of 5 μl of ATP-mix containingin a final volume 10 μL 10 mM TRIS-HCl pH 7.5, 3 mM MgCl2, 50 mM NaCl,0.05% CHAPS, 1 mM DTT and 1 μM ATP, and occurred at room temperature.Reactions were stopped with 10 μl of KinaseGlo and plates were read 10minutes later in a Synergy2 reader using an integration time of 0.1seconds per well. The luminescence-based ATP detection reagent KinaseGlowas obtained from Promega, (Cat. No. V6714, Lot No. 236161) throughCatalys, Wallisellen, Switzerland.

IC50 values of the percentage inhibition of each compound at 8concentrations (usually 10, 3.0, 1.0, 0.3, 0.1, 0.030, 0.010 and 0.003μM) n=2 were derived by fitting a sigmoidal dose response curve to aplot of assay readout over inhibitor concentration.

Example Vps34 IC50 (μM)  6a 1.00  6b 0.264  6c 0.775  6d 0.728  6e 0.111 6f 4.00 10a 0.0175 10b 0.02 10c 0.0755 10d 0.072 10e 0.0785 10f 0.045510g 0.2365 10h 0.2575 10i 0.035 10j 0.029 10k 0.2755 10l 0.0805 10m0.0115 10n 0.031 10o 0.0315 10p 0.2105 10q 0.053 10r 0.085 10s 0.051510t 0.015 10u 0.0905 10v 0.214 11 0.1065 12a 0.0345 12b 0.5695 12c0.0455 13 0.007 14a 0.115 14b 0.286 14c 0.037 14d 0.133 14e 1.10 14f0.722 14g 0.398 14h 1.36 14i 0.348 14j 0.411 14k 0.857 14l 0.048 14m0.119 14n 0.439 14o 0.374 14p* 5.17 14q* 0.862 14r* 1.54 14s* 7.13 15a0.577 15b 0.199 15c 6.62 15d 1.50 15e 0.196 15f Not determined 15g 2.2315h 0.048 15i 0.924 15j 0.053 15k 0.781 15l 0.025 15m 0.101 15n 0.06215o 0.057 15p 0.122 15q 1.29 15r Not determined 15s 1.66 15t 0.187 15u0.104 15v 0.193 15w 0.036 15x 0.027 15y 0.231 16a 0.004 16b 0.025 16c0.150 16d 0.026 16e 0.105 16f 0.138 16g 0.872 21 0.02225 22 0.031 230.1305 24 0.096 25 0.117 37a 0.031 37b Not determined

Thus while there have been described what are presently believed to bepreferred embodiments of the invention, those skilled in the art willrealize that changes and modifications may be made thereto withoutdeparting from the spirit of the invention, and it is intended to claimall such changes and modifications as fall within the true scope of theinvention.

What is claimed is:
 1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein R¹ is C₁₋₆alkyl,NR³R⁶, C₁₋₆alkoxy, or —S—C₁₋₆alkyl; R² is C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, a C₆₋₁₄aryl group, a C₃₋₁₄cycloalkyl group, a 5 to −14membered heteroaryl containing 1 to 3 heteroatoms each independentlyselected from N, O, and S, C₁₋₆alkoxy, C₂₋₆-alkenyloxy, C₂₋₆-alkynyloxy,C₁₋₆alkyl-O—R²⁷, C₁₋₆alkyl-C₃₋₁₄cycloalkyl,C₁₋₆alkyl-O—C₀₋₆alkyl-C₆₋₁₄aryl, C₁₋₆alkyl-O—SiR⁸R⁹R¹⁰, halogen, orC₁₋₆haloalkyl, wherein R² may be unsubstituted or substituted with OH,C1-6alkoxy, or halogen; R⁴ and R⁵ are independently H, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, a C₆₋₁₄aryl group, a C₃₋₁₄cycloalkyl group, a3-14 membered cycloheteroalkyl group, a 5-14 membered heteroaryl group,C₁₋₆alkoxy, OH, C₁₋₆alkylNR¹¹R¹², C₁₋₆alkyl-O—R¹³,C₁₋₆alkyl-5-14membered heteroaryl group, or C(O)—C₁₋₆alkyl, wherein saidC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₆₋₁₄aryl group, C₃₋₁₄cycloalkylgroup, 3-14 membered cycloheteroalkyl group, 5-14 membered heteroarylgroup, C₁₋₆alkoxy, C₁₋₆alkyl-NR¹¹R¹², C₁₋₆alkylOR¹³, C₁₋₆alkyl-5-14membered heteroaryl group, or C(O)—C₁₋₆alkyl may be optionallysubstituted by one or more from the group of halogen, a 5-14 memberedheteroaryl group, OH, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkylOR²⁷,C₁₋₆alkoxy, NR¹⁴R¹⁵, CONR¹⁶R¹⁷, NR¹⁸COR¹⁹, NR²⁰COOR²¹, COR²², COOR²³,—CN, SO₂R²⁶, or NR²⁴SO₂R²⁵; R³ and R⁶ are independently H, C₁₋₆alkyl,C₁₋₆alkyl-aryl, C₁₋₆alkoxy, a C₃₋₁₄cycloalkyl group, a 3-14 memberedcycloheteroalkyl group, a C₆₋₁₄aryl group, a 5-14 membered heteroarylgroup, or C₁₋₆alkyl-O—R⁸, wherein C₁₋₆alkyl, C₁₋₆alkyl-aryl, C₁₋₆alkoxy,a C₃₋₁₄cycloalkyl group, a 3-14 membered cycloheteroalkyl group, aC₆₋₁₄aryl group, a 5-14 membered heteroaryl group, or C₁₋₆alkyl-O—R⁸,may be substituted by one of more of C₁₋₆alkyl, or OH; R¹¹ and R¹² arethe same or different, and independently are selected from hydrogen,C₁₋₆alkyl, a C₃₋₈cycloalkyl group, a C₆₋₁₄ aryl group, a 5-14 memberedheteroaryl group, and a 3-14 membered cycloheteroalkyl group, or NR¹¹R¹²forms a non-aromatic four to seven membered ring optionally containing asecond heteroatom selected from O, N and S, and optionally substitutedby one or more substituents R²⁸; R⁷ and R^(7a) are independently H orC₁₋₆alkyl n is 0, 1, or 2; and R⁸, R⁹, R¹⁰, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶,R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, and R²⁷, and R²⁸ areindependently H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, a C₆₋₁₄ arylgroup, A C₃₋₁₄ cycloalkyl group, a 3-14 membered cycloheteroalkyl group,or a 5-14 membered heteroaryl group.
 2. The compound of formula (I)according to claim 1, wherein R¹ is C₁₋₆alkyl, NR³R⁶, or C₁₋₆alkoxy, andR³ and R⁶ are independently H, C₁₋₆alkyl, C₁₋₆alkyl-aryl, aC₃₋₁₄cycloalkyl group, C₁₋₆alkylOH, C₁₋₆alkylOC₁₋₆alkyl, or a 3-14membered cycloheteroalkyl group.
 3. The compound of formula (I)according to claim 1 wherein R¹ is methyl, ethyl, propyl, methoxy,ethoxy, methyl-phenyl, NH₂, NH-pentyl-OH, NHbutyl, NHCH₃, orNHisopropyl.
 4. The compound of formula (I) according to claim 1 whereinR¹ is NH₂, NH-pentyl-OH, NHbutyl, NHCH₃, or NHisopropyl.
 5. The compoundof formula (I) according to claim 1 wherein R² is C₁₋₆alkyl, aC₃₋₁₄cycloalkyl group, or C₁₋₆alkyl-C₃₋₁₄cycloalkyl.
 6. The compound offormula (I) according to claim 1 wherein R² is methyl, ethyl, propyl,phenyl, cyclopropyl, cyclopentyl, cyclohexyl, methoxy, —CH₂—O—CH₃,—CH₂-cyclopropyl, —CH₂-cyclobutyl, —CH₂-cyclopentyl, —CH₂-cyclohexyl,—CH₂CH₂-cyclopropyl, —CH₂CH₂-cyclobutyl, —CH₂CH₂-cyclopentyl,—CH₂CH₂-cyclohexyl, or —CH₂—O—CH₂-phenyl.
 7. The compound of formula (I)according to claim 1 wherein R² is —CH₂-cyclopropyl.
 8. The compound offormula (I) according to claim 1 wherein R⁴ and R⁵ are independently H,a C₆₋₁₄aryl group, C₃₋₁₄cycloalkyl group, a 3-14 memberedcycloheteroalkyl group, or a 5-14 membered heteroaryl group wherein saidC₆₋₁₄aryl group, C₃₋₁₄cycloalkyl group, 3-14 membered cycloheteroalkylgroup, or 5-14 membered heteroaryl group, is optionally mono- ordi-substituted by one or more of halogen, OH, C₁₋₆alkyl, C₁₋₆haloalkyl,C₁₋₆alkylOH, C₁₋₆alkoxy, NR¹⁴R¹⁵, CONR¹⁶R¹², NR¹⁸COR¹⁹, NR²⁰COOR²¹,COR²², COOR²³, or NR²⁴SO₂R²⁵.
 9. The compound of formula (I) accordingto claim 1 where one of R⁴ or R⁵ is H, and the other is methyl, ethyl,propyl, phenyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl,pyrrolidinyl, tetrahydropyranyl, pyridinyl, pyrimidinyl, or pyridazinyl;each of which may be unsubstituted or substituted with one or more ofhalogen, a 5-14 membered heteroaryl group, OH, C₁₋₆alkyl, C₁₋₆haloalkyl,C₁₋₆alkylOR²², C₁₋₆alkoxy, NR¹⁴R¹⁵, CONR¹⁶R¹⁷, NR¹⁸COR¹⁹, NR²⁰COOR²¹,COR²², COOR²³, —CN, SO₂R²⁶, —O—, or NR²⁴SO₂R²⁵.
 10. The compound offormula (I) according to claim 1 where one of R⁴ and R⁵ is H, and theother is phenyl or pyridinyl, each of which may be unsubstituted orsubstituted with one or more of F, Cl, OH, methyl, ethyl, CN, or CF₃.11. The compound of formula (I) according to claim 1 where R² is H and nis
 0. 12. A compound of Formula II,

or a pharmaceutically acceptable salt thereof, wherein R¹ is(C₁-C₆)alkyl, —OCH₃, —NH₂, —NH(C₁-C₆)alkyl, —NHCH₂(phenyl), —NHCH₂CH₂OH,—NHCH₂CH(OH)CH₃, —NHCH(CH₃)CH₂OH, —NHCH₂CH(CH₃)₂OH, —NHCH₂CH₂OCH₃,—NH(C₃-C₆)cycloalkyl, phenethylamino-, tetrahydropyranylamino-, or—SCH₃; R² is (C₁-C₆)alkyl, —CF₃, —CH₂(cyclopropyl), —CH₂OH, or—CH₂OCH₂(phenyl); R⁴ is H; and R⁵ is (i) —(CH₂)_(n)—R^(5a), where n is0, 1 or 2 and R^(5a) is pyridinyl, 6-methoxypyridin-3-yl, furanyl,imidazolyl, isoxazolyl, thiazolyl, thiadiazolyl, quinolinyl, 1H-indolyl,benzo[d][1,3]dioxolyl, morpholinyl, tetrahydropyranyl, or piperidinyl,where said chemical moiety is optionally substituted with a methyl orhalo; or (ii) (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, or phenyl, wherein said(C₁-C₆)alkyl, said (C₃-C₆)cycloalkyl, and said phenyl are optionallysubstituted with one to two substituents each independently selectedfrom F, Cl, —CH₃, —CN, —OH, —OCH₃, —NHC(O)—(C₁-C₄)alkyl, —NH₂, —N(CH₃)₂,—NHSO₂CH₃, —C(O)CH₃, —C(O)OH, or —SO₂CH₃.
 13. The compound according toclaim 12 wherein n is
 0. 14. The compound according to claim 1 which is1-(4′-(cyclopropylmethyl)-2-(pyridin-4-ylamino)-4,5′-bipyrimidin-2′-ylamino)-2-methylpropan-2-olhaving the following formula:

or a pharmaceutically acceptable salt thereof.
 15. The compoundaccording to claim 1 which is4′-Cyclopropylmethyl-N²-pyridin-4-yl-[4,5′]bipyrimidinyl-2,2′-diaminehaving the following formula:

or a pharmaceutically acceptable salt thereof.
 16. The compoundaccording to claim 1 which is4′-Benzyloxymethyl-N²-pyridin-4-yl-[4,5′]bipyrimidinyl-2,2′-diaminehaving the following formula:

or a pharmaceutically acceptable salt thereof.
 17. The compoundaccording to claim 1 which isN2-(pyridin-4-yl)-4′-(trifluoromethyl)-4,5′-bipyrimidine-2,2′-diaminehaving the following formula:

or a pharmaceutically acceptable salt thereof.
 18. A pharmaceuticalcomposition comprising a compound of formula I according to claim 1 anda pharmaceutically acceptable carrier or excipient.
 19. A pharmaceuticalcomposition comprising a compound of formula I according to claim 1 incombination with a second active agent, and a pharmaceuticallyacceptable carrier or excipient.